1. Field of the Invention
The present invention relates to imidazolidine derivatives of the formula I, 
in which B, E, W, Z, R, R0, R2, R3, e, and h have the meanings indicated below. The compounds of the formula I are valuable pharmaceutically active compounds, which are suitable, for example, for the therapy and prophylaxis of inflammatory disorders, for example, of rheumatoid arthritis, or of allergic disorders The compounds of the formula I are inhibitors of the adhesion and migration of leucocytes and/or are antagonists of the integrin adhesion receptor VLA-4. They are generally suitable for the therapy or prophylaxis of illnesses which are caused by or associated with an undesired extent of leucocyte adhesion and/or leucocyte migration, or in illnesses in which cell-cell or cell-matrix interactions which are based on VLA-4 receptor/ligand interactions. The invention furthermore relates to processes for the preparation of the compounds of the formula I, their use in the therapy and prophylaxis of the disease states mentioned, and pharmaceutical preparations which contain compounds of the formula I.
2. Description of Related Art
The integrins are a group of adhesion receptors which play an important part in cell-cell-binding and cell-extracellular matrix-binding processes. They have an xcex1xcex2-heterodimeric structure and exhibit a wide cellular distribution and are highly conserved in evolution. The integrins include, for example, the fibrinogen receptor on platelets, which interacts especially with the RGD sequence of fibrinogen, or the vitronectin receptor on osteoclasts, which interacts especially with the RGD sequence of vitronectin or of osteopontin. The integrins are divided into three major groups, the xcex22 subfamily with the representatives LFA-1, Mac-1 and p150/95, which are responsible in particular for cell-cell interactions of the immune system, and the subfamilies xcex21 and xcex23, whose representatives mainly mediate cell adhesion to components of the extracellular matrix (Ruoslahti, Annu. Rev. Biochem. 1988, 57, 375). The integrins of the xcex21 subfamily, also called VLA proteins (very late (activation) antigen), include at least six receptors which interact specifically with fibronectin, collagen and/or laminin as ligands. Within the VLA family, the integrin VLA-4 (xcex14xcex21) is a typical, insofar as it is mainly restricted to lymphoid and myeloid cells where it is responsible for cell-cell interactions with a large number of other cells. For example, VLA-4 mediates the interaction of T and B lymphocytes with the heparin II-binding fragment of human plasma fibronectin (FN). The binding of VLA-4 with the heparin II-binding fragment of plasma fibronectin is especially based on an interaction with an LDVP sequence. In contrast to the fibrinogen or vitronectin receptor, VLA-4 is not a typical RGD-binding integrin (Kilger and Holzmann, J. Mol. Meth. 1995, 73, 347).
The leucocytes circulating in the blood normally exhibit only a low affinity for the vascular endothelial cells which line the blood vessels. Cytokines which are released from inflamed tissue cause the activation of endothelial cells and thus the expression of a large number of cell surface antigens. These include, for example, the adhesion molecules ELAM-1 (endothelial cell adhesion molecule-1; also designated as E-selectin), which, inter alia, binds neutrophils, ICAM-1 (intercellular adhesion molecule-1), which interacts with LFA-1 (leucocyte function-associated antigen 1) on leucocytes, and VCAM-1 (vascular cell adhesion molecule-1), which binds various leucocytes, inter alia lymphocytes (Osborn et al., Cell 1989, 59, 1203). VCAM-1, like ICAM-1, is a member of the immunoglobulin gene superfamily. VCAM-1 (first known as INCAM-110) was identified as an adhesion molecule which is induced on endothelial cells by inflammatory cytokines such as TNF and IL-1 and lipopolysaccharides (LPS). Elices et al., (Cell 1990, 60, 577) showed that VLA-4 and VCAM-1 form a receptor-ligand pair which mediates the adhesion of lymphocytes to activated endothelium. The binding of VCAM-1 to VLA-4 does not take place via an interaction of VLA-4 with an RGD sequence; this sequence is not contained in VCAM-1 (Bergelson et al., Current Biology 1995, 5, 615). VLA-4, however, also occurs on other leucocytes, and the adhesion of leucocytes other than lymphocytes is also mediated via the VCAM-1/VLA-4 adhesion mechanism. VLA-4 thus represents an individual example of a xcex21 integrin receptor which, via the ligands VCAM-1 and fibronectin, plays an important part both in cell-cell interactions and in cell-extracellular matrix interactions.
The cytokine-induced adhesion molecules play an important part in the recruitment of leucocytes into extravascular tissue regions. Leucocytes are recruited into inflammatory tissue regions by cell adhesion molecules which are expressed on the surface of endothelial cells and serve as ligands for leucocyte cell surface proteins or protein complexes (receptors) (the terms ligand and receptor can be considered interchangeable here.) Leucocytes from the blood must first adhere to endothelial cells before they can migrate into the synovium. Since VCAM-1 binds to cells which carry the integrin VLA-4 (xcex14xcex21), such as eosinophils, T and B lymphocytes, monocytes or neutrophils, the VCAM-1/VLA-4 mechanism has the function of recruiting cells of this type from the blood stream into areas of infection and inflammatory foci (Elices et al., Cell 1990, 60, 577; Osborn, Cell 1990, 62, 3; Issekutz et al., J. Exp. Med. 1996, 183, 2175).
The VCAM-1/VLA-4 adhesion mechanism has been connected with a number of physiological and pathological processes. Apart from cytokine-activated endothelium, VCAM-1 is additionally expressed, inter alia, by the following cells: myoblasts, lymphoid dendritic cells and tissue macrophages, rheumatoid synovium, cytokine-stimulated neural cells, parietal epithelial cells of the Bowman""s capsule, the renal tubular epithelium, inflamed tissue during heart and kidney transplant rejection and by intestinal tissue in graft-versus-host disease. VCAM-1 is also expressed on those tissue areas of the arterial endothelium which correspond to early arteriosclerotic plaques of a rabbit model. Additionally, VCAM-1 is expressed on follicular dendritic cells of human lymph nodes and is found on stroma cells of the bone marrow, for example in the mouse. The latter finding points to a function of VCAM-1 in B-cell development. Apart from cells of hematopoietic origin, VLA-4 is also found, for example, on melanoma cell lines, and the VCAM-1/VLA-4 adhesion mechanism is connected with the metastasis of such tumors (Rice et al., Science 1989, 246, 1303).
The main form in which VCAM-1 occurs in vivo on endothelial cells and which is the dominant form in vivo is designated as VCAM-7D and carries seven immunoglobulin domains. The domains 4, 5 and 6 are similar in their amino acid sequences to the domains 1, 2 and 3. The fourth domain is removed in a further form, consisting of six domains, designated here as VCAM-6D, by alternative splicing. VCAM-6D can also bind VLA-4-expressing cells.
Further details on VLA-4, VCAM-1, integrins and adhesion proteins are found, for example, in the articles by Kilger and Holzmann, J. Mol. Meth. 1995, 73, 347; Elices, Cell Adhesion in Human Disease, Wiley, Chichester 1995, p. 79; and Kuijpers, Springer Semin. Immunopathol. 1995, 16, 379.
On account of the role of the VCAM-1/VLA-4 mechanism in cell adhesion processes, which are important, for example, in infections, inflammations or atherosclerosis, attempts have been made to intervene in these adhesion processes to control illnesses, in particular, for example, in inflammation (Osborn et al., Cell 1989, 59, 1203). A method of doing this is the use of monoclonal antibodies which are directed against VLA-4. Monoclonal antibodies (mAB) of this type, which act as VLA-4 antagonists to block the interaction between VCAM-1 and VLA-4, are known. Thus, for example, the anti-VLA-4 mAB HP2/1 and HP1/3 inhibit the adhesion of VLA-4-expressing Ramos cells (B-cell-like cells) to human umbilical cord endothelial cells and to VCAM-1-transfected COS cells. The anti-VCAM-1 mAB 4B9 likewise inhibits the adhesion of Ramos cells, Jurkat cells (T-cell-like cells) and HL60 cells (granulocyte-like cells) to COS cells transfected expressing VCAM-6D and VCAM-7D in vitro data with antibodies directed against the xcex14 subunit of VLA-4 show that adhesion of lymphocytes to synovial endothelial cells is blocked, an adhesion which plays a part in rheumatoid arthritis (van Dinther-Janssen et al., J. Immunol. 1991, 147, 4207).
In vivo experiments have shown that an experimental autoimmune encephalomyelitis can be inhibited by anti-xcex14 mAB. The migration of leucocytes into an inflammatory focus is likewise blocked by a monoclonal antibody against the xcex14 chain of VLA-4. The influencing of the VLA-4-dependent adhesion mechanism by antibodies was also investigated in an asthma model in order to investigate the role of VLA-4 in the recruitment of leucocytes into inflamed lung tissue (U.S. Ser. No. 07/821,768; EP-A-626 861). The administration of anti-VLA-4 antibodies inhibited the late-phase reaction and airway overreaction in allergic sheep.
The VLA-4-dependent cell adhesion mechanism was also investigated in a primate model of inflammatory bowel disease (IBD). In this model, which corresponds to ulcerative colitis in man, the administration of anti-VLA-4 antibodies resulted in a significant reduction in the acute inflammation.
Moreover, it was possible to show that VLA-4-dependent cell adhesion plays a part in the following clinical conditions including the following chronic inflammatory processes: rheumatoid arthritis (Cronstein and Weismann, Arthritis Rheum. 1993, 36, 147; Elices et al., J. Clin. Invest. 1994, 93, 405), diabetes mellitus (Yang et al., Proc. Natl. Acad. Sci. USA 1993, 90, 10494), systemic lupus erythematosus (Takeuchi et al., J. Clin. Invest. 1993, 92, 3008), allergies of the delayed type (type IV allergy) (Elices et al., Clin. Exp. Rheumatol 1993, 11, S77), multiple sclerosis (Yednock et al., Nature 1992, 356, 63), malaria (Ockenhouse et al., J. Exp. Med. 1992, 176, 1183), arteriosclerosis (O""Brien et al., J. Clin. Invest. 1993, 92, 945), transplantation (Isobe et al., Transplantation Proceedings 1994, 26, 867-868), various malignancies, for example melanoma (Renkonen et al., Am. J. Pathol. 1992, 140, 763), lymphoma (Freedman et al., Blood 1992, 79, 206) and others (Albelda et al., J. Cell Biol. 1991, 114, 1059).
VLA-4 blocking by suitable antagonists accordingly offers effective therapeutic possibilities, in particular, for example, of treating various inflammatory conditions including asthma and IBD. The particular relevance of VLA-4 antagonists for the treatment of rheumatoid arthritis in this case results, as already stated, from the fact that leucocytes from the blood must first adhere to endothelial cells before they can migrate into the synovium, and that the VLA-4 receptor plays a part in this adhesion. The fact that VCAM-1 is induced by inflammatory agents on endothelial cells (Osborn, Cell 1990, 62, 3; Stoolman, Cell 1989, 56, 907), and the recruitment of various leucocytes into areas of infection and inflammatory foci has already been discussed above. In this respect, T cells adhere to activated endothelium mainly via the LFA-1/ICAM-1 and VLA-4/VCAM-1 adhesion mechanisms (Springer, Cell 1994, 76, 301). On most synovial T cells, the binding capacity of VLA-4 for VCAM-1 is increased in rheumatoid arthritis (Postigo et al., J. Clin. Invest. 1992, 89, 1445). Additionally, an increased adhesion of synovial T cells to fibronectin has been observed (Laffon et al., J. Clin. Invest. 1991, 88, 546; Morales-Ducret et al., J. Immunol. 1992, 149, 1424). VLA-4 is upregulated both in the course of its expression and with respect to its function on T lymphocytes of the rheumatoid synovial membrane. The blocking of the binding of VLA-4 to its physiological ligands VCAM-1 and fibronectin makes possible an effective prevention or alleviation of articular inflammatory processes. This is also confirmed by experiments with the antibody HP2/1 on Lewis rats with adjuvant arthritis, in which an effective prevention of illness has been observed (Barbadillo et al., Springer Semin. Immunopathol. 1995, 16, 427). VLA-4 is thus an important therapeutic target molecule.
The abovementioned VLA-4 antibodies and the use of antibodies as VLA-4 antagonists are described in the Patent Applications WO-A-93/13798, WO-A-93/15764, WO-A-94/16094, WO-A-94/17828, and WO-A-95/19790. In the Patent Applications WO-A-94/15958, WO-A-95/15973, WO-A-96/00581, WO-A-96/06108 and WO-A-96/20216, peptide compounds are described as VLA-4 antagonists. The use of antibodies and peptide compounds as pharmaceuticals, however, has some disadvantages, for example lack of oral availability, rapid degradation or immunogenicity on longer-term use. There is thus a need for VLA-4 antagonists having improved properties for use in therapy and prophylaxis.
WO-A-95/14008, WO-A-94/21607, WO-A-93/18057, EP-A-449 079, EP-A-530 505 (U.S. Pat. No. 5,389,614), EP-A-566 919 (U.S. Pat. No. 5,397,796), EP-A-580 008 (U.S. Pat. No. 5,424,293) and EP-A-584 694 (U.S. Pat. No. 5,554,594) describe substituted 5-membered ring heterocycles which have an amino, amidino or guanidino function at the N-terminal end of the molecule and which exhibit platelet aggregation-inhibiting actions. EP-A-796 855 (European Patent Application 97103712.2) describes further heterocycles which are inhibitors of bone resorption. EP-A-842 943, EP-A-842 945 and EP-A-842 944 (German Patent Applications 19647380.2, 19647381.0 and 19647382.9) describe that certain compounds from this series and certain further compounds surprisingly also inhibit leucocyte adhesion and are VLA-4 antagonists. However, the selected compounds of the formula I according to the present invention, which are distinguished by their VLA-4 antagonism and/or their inhibitory action on leucocyte adhesion and leucocyte migration and are the subject of the present invention, are not disclosed or suggested in the applications mentioned.
The present invention thus relates to compounds of the formula I, 
in which
W is R1xe2x80x94Axe2x80x94C(R13) or R1xe2x80x94CHxe2x95x90C;
Z is oxygen or sulfur;
A is a direct bond or (C1-C2)-alkylene;
B is a divalent radical selected from the group of (C1-C6)-alkylene, (C2-C6)-alkenylene, phenylene, phenylene-(C1-C3)-alkyl, (C1-C3)-alkylenephenyl, where the divalent (C1-C6)-alkylene radical can be unsubstituted or substituted by a radical selected from the group consisting of (C1-C8)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl, (C3-C10)-cycloalkyl, (C3-C10)-cycloalkyl-(C1-C6)-alkyl, optionally substituted (C6-C14)-aryl, (C6-C14)-aryl-(C1-C6)-alkyl optionally substituted in the aryl radical, optionally substituted heteroaryl, and heteroaryl-(C1-C6)-alkyl optionally substituted in the heteroaryl radical;
E is tetrazolyl, (R8O)2P(O), HOS(O)2, R9NHS(O)2, or R10CO;
R is hydrogen, (C1-C8)-alkyl, (C3-C12)-cycloalkyl, (C3-C12)-cycloalkyl-(C1-C8)-alkyl, optionally substituted (C6-C14)-aryl, (C6-C14)-aryl-(C1-C8)-alkyl optionally substituted in the aryl radical, optionally substituted heteroaryl or heteroaryl-(C1-C8)-alkyl optionally substituted in the heteroaryl radical;
R0 is hydrogen, (C1-C8)-alkyl, (C3-C12)-cycloalkyl, (C3-C12)-cycloalkyl-(C1-C8)-alkyl, (C6-C12)-bicycloalkyl, (C6-C12)-bicycloalkyl-(C1-C8)-alkyl, (C6-C12)-tricycloalkyl, (C6-C12)-tricycloalkyl-(C1-C8)-alkyl, optionally substituted (C6-C14)-aryl, (C6-C14)-aryl-(C1-C8)-alkyl optionally substituted in the aryl radical, optionally substituted heteroaryl, heteroaryl-(C1-C8)-alkyl optionally substituted in the heteroaryl radical, Hxe2x80x94CO, (C1-C8)-alkyl-CO, (C3-C12)-cycloalkyl-CO, (C3-C12)-cycloalkyl-(C1-C8)-alkyl-CO, (C6-C12)-bicycloalkyl-CO, (C6-C12)-bicycloalkyl-(C1-C8)-alkyl-CO, (C6-C12)-tricycloalkyl-CO, (C6-C12)-tricycloalkyl-(C1-C8)-alkyl-CO, optionally substituted (C6-C14)-aryl-CO, (C6-C14)-aryl-(C1-C8)-alkyl-CO optionally substituted in the aryl radical, optionally substituted heteroaryl-CO, heteroaryl-(C1-C8)-alkyl-CO optionally substituted in the heteroaryl radical, (C1-C8)-alkyl-S(O)n, (C3-C12)-cycloalkyl-S(O)n, (C3-C12)-cycloalkyl-(C1-C8)-alkyl-S(O)n, (C6-C12)-bicycloalkyl-S(O)n, (C6-C12)-bicycloalkyl-(C1-C8)-alkyl-S(O)n, (C6-C12)-tricycloalkyl-S(O)n, (C6-C12)-tricycloalkyl-(C1-C8)-alkyl-S(O)n, optionally substituted (C6-C14)-aryl-S(O)n, (C6-C14)-aryl-(C1-C8)-alkyl-S(O)n optionally substituted in the aryl radical, optionally substituted heteroaryl-S(O)n or heteroaryl-(C1-C8)-alkyl-S(O)n optionally substituted in the heteroaryl radical, where n is 1 or 2;
R1 is an optionally substituted radical selected from the group consisting of phenyl, furyl, thienyl, pyrrolyl, imidazolyl and pyridyl, where each of these radicals can also be benzo-fused;
R2 is hydrogen, (C1-C8)-alkyl, optionally substituted (C6-C14)-aryl, (C6-C14)-aryl-(C1-C8)-alkyl optionally substituted in the aryl radical or (C3-C8)-cycloalkyl;
R3 is hydrogen, (C1-C8)-alkyl, optionally substituted (C6-C14)-aryl, (C6-C14)-aryl-(C1-C8)-alkyl optionally substituted in the aryl radical, optionally substituted heteroaryl, heteroaryl-(C1-C8)-alkyl optionally substituted in the heteroaryl radical, (C3-C8)-cycloalkyl, (C3-C8)-cycloalkyl-(C1-C8)-alkyl, (C6-C12)-bicycloalkyl, (C6-C12)-bicycloalkyl-(C1-C8)-alkyl, (C6-C12)-tricycloalkyl, (C6-C12)-tricycloalkyl-(C1-C8)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl, R11NH, CON(CH3)R4, CONHR4, COOR15, CON(CH3)R15 or CONHR15;
R4 is hydrogen or (C1-C10)-alkyl which can optionally be monosubstituted or polysubstituted by identical or different radicals selected from the group consisting of hydroxyl, (C1-C8)-alkoxy, R5, optionally substituted (C3-C8)-cycloalkyl, hydroxycarbonyl, aminocarbonyl, mono- or di-((C1-C18)-alkyl)-aminocarbonyl, (C6-C14)-aryl-(C1-C8)-alkoxycarbonyl which can also be substituted in the aryl radical, (C1-C8)-alkoxycarbonyl, Het- CO, R6xe2x80x94CO, tetrazolyl, and trifluoromethyl;
R5 is optionally substituted (C6-C14)-aryl, (C6-C14)-aryl-(C1-C8)-alkyl optionally substituted in the aryl radical, or an optionally substituted monocyclic or bicyclic 5-membered to 12-membered heterocyclic ring which can be aromatic, partially hydrogenated or completely hydrogenated and which can contain one, two or three identical or different heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur;
R6 is the radical of a natural or unnatural amino acid, imino acid, optionally Nxe2x80x94(C1-C8)-alkylated or Nxe2x80x94((C6-C14)-aryl-(C1-C8)-alkylated) azaamino acid which can also be substituted in the aryl radical, or the radical of a dipeptide, and their esters and amides, where free functional groups can be protected by protective groups customary in peptide chemistry;
R8 is hydrogen, (C1-C18)-alkyl, optionally substituted (C6-C14)-aryl or (C6-C14)-aryl-(C1-C8)-alkyl which can also be substituted in the aryl radical;
R9 is hydrogen, aminocarbonyl, (C1-C18)-alkylaminocarbonyl, (C3-C8)-cycloalkylaminocarbonyl, optionally substituted (C6-C14)-arylaminocarbonyl, (C1-C18)-alkyl, optionally substituted (C6-C14)-aryl or (C3-C8)-cycloalkyl;
R10 is hydroxyl, (C1-C18)-alkoxy, (C6-C14)-aryl-(C1-C8)-alkoxy which can also be substituted in the aryl radical, optionally substituted (C6-C14)-aryloxy, (C1-C8)-alkylcarbonyloxy-(C1-C6)-alkoxy, (C6-C14)-arylcarbonyloxy-(C1-C5)-alkoxy, amino or mono- or di-((C1-C18)-alkyl)-amino;
R11 is hydrogen, R12a, R12axe2x80x94CO, Hxe2x80x94CO, R12axe2x80x94Oxe2x80x94CO, R12bxe2x80x94CO, R12bxe2x80x94CS, R12axe2x80x94S(O)2 or R12bxe2x80x94S(O)2;
R12a is (C1-C18)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl, (C3-C12)-cycloalkyl, (C3-C12)-cycloalkyl-(C1-C8)-alkyl, optionally substituted (C6-C14)-aryl, (C6-C14)-aryl-(C1-C8)-alkyl optionally substituted in the aryl radical, optionally substituted heteroaryl, heteroaryl-(C1-C8)-alkyl optionally substituted in the heteroaryl radical, or the radical R15;
R12b is amino, di-((C1-C18)-alkyl)-amino or R12axe2x80x94NH;
R13 is hydrogen, (C1-C6)-alkyl, optionally substituted (C6-C14)-aryl, (C6-C14)-aryl-(C1-C6)-alkyl optionally substituted in the aryl radical, (C3-C8)-cycloalkyl or (C3-C8)-cyclo-(C1-C6)-alkyl;
R15 is R16xe2x80x94(C1-C6)-alkyl or R16;
R16 is a 6-membered to 24-membered bicyclic or tricyclic radical which is saturated or partially unsaturated and which can also contain one, two, three or four identical or different heteroatoms selected from the group of nitrogen, oxygen and sulfur and which can also be substituted by one or more identical or different substituents from the group consisting of (C1-C4)-alkyl and oxo;
Het is the radical of a 5-membered to 10-membered, saturated monocyclic or polycyclic heterocycle bonded via a ring nitrogen atom, which can contain one, two, three or four identical or different additional ring heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur and which can optionally be substituted on carbon atoms and on additional ring nitrogen atoms, where substituents on additional ring nitrogen atoms can be identical or different radicals from the group consisting of hydrogen, Rh, HCO, RhCO and RhOxe2x80x94CO and Rh is (C1-C8)-alkyl, (C3-C8)-cycloalkyl, (C3-C8)-cycloalkyl-(C1-C8)-alkyl, optionally substituted (C6-C14)-aryl or (C6-C14)-aryl-(C1-C8)-alkyl optionally substituted in the aryl radical;
e and h independently of one another are 0 or 1;
in any of their stereoisomeric forms and mixtures thereof in any ratios, and any of their physiologically tolerable salts.
In the compounds of the invention, alkyl radicals can be straight-chain or branched. This also applies if alkyl radicals carry substituents or occur as substituents of other radicals, for example in alkoxy radicals, alkoxycarbonyl radicals, or arylalkyl radicals. The same applies to alkylene radicals. Examples of suitable (C1-C18)-alkyl radicals are methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-decyl, n-undecyl, n-dodecyl, n-tridecyl, n-pentadecyl, n-hexadecyl, n-heptadecyl, n-octadecyl, isopropyl, isobutyl, isopentyl, isohexyl, 3-methylpentyl, neopentyl, neohexyl, 2,3,5-trimethylhexyl, sec-butyl, tert-butyl, and tert-pentyl. Preferred alkyl radicals are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, and isohexyl. Examples of alkylene radicals are methylene, ethylene, tri-, tetra-, penta- and hexamethylene or methylene or ethylene substituted by an alkyl radical, for example, methylene which is substituted by a methyl group, an ethyl group, an isopropyl group, an isobutyl group, a tert-butyl group, an n-pentyl group, an isopentyl group or an n-hexyl group, or, for example, ethylene which can be substituted either on one carbon atom or on the other carbon atom or alternatively on both carbon atoms.
Alkenyl radicals and alkenylene radicals as well as alkynyl radicals can also be straight-chain or branched. Examples of alkenyl radicals are vinyl, 1-propenyl, allyl, butenyl, 3-methyl-2-butenyl, examples of alkenylene radicals are vinylene or propenylene and examples of alkynyl radicals are ethynyl, 1-propynyl, or propargyl.
Cycloalkyl radicals are, in particular, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl and cyclododecyl, which, can also be substituted, for example, by (C1-C4)-alkyl. Examples of substituted cycloalkyl radicals include 4-methylcyclohexyl and 2,3-dimethylcyclopentyl. Cycloalkylene radicals may be substituted in the same way.
Bicycloalkyl radicals, tricycloalkyl radicals and the 6-membered to 24-membered bicyclic and tricyclic radicals representing R16 are formally obtained by abstraction of a hydrogen atom from bicycles or tricycles. The basic bicycles and tricycles contain only carbon atoms as ring members, they can thus be bicycloalkanes or tricycloalkanes, but in the case of the radicals representing R16 they can also contain one to four identical or different heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur; they can thus be aza-, oxa- and tniabicyclo- and -tricycloalkanes. If heteroatoms are contained, preferably one or two heteroatoms, in particular nitrogen atoms or oxygen atoms, are contained. The heteroatoms can occupy any desired positions in the bicyclic or tricyclic structure; they can be located in the bridges or, in the case of nitrogen atoms, also on the bridgeheads. Both the bicycloalkanes and tricycloalkanes and their heteroanalogs can be completely saturated or can contain one or more double bonds; preferably they contain one or two double bonds or are, in particular, completely saturated. Both the bicycloalkanes and tricycloalkanes as well as the heteroanalogs and both the saturated and the unsaturated representatives can be unsubstituted or can be substituted in any desired suitable positions by one or more oxo groups and/or one or more identical or different (C1-C4)-alkyl groups, for example, methyl groups or isopropyl groups, preferably methyl groups. The free bond of the bicyclic or tricyclic radical can be located in any desired position of the molecule, and the radical can thus be bonded via a bridgehead atom or an atom in a bridge. The free bond can also be located in any desired stereochemical position, for example, in an exo position or an endo position.
Examples of parent structures of bicyclic ring systems, from which a bicyclic radical can be derived, are norbornane (=bicyclo[2.2.1]heptane), bicyclo[2.2.2]octane and bicyclo[3.2.1]octane, examples of heteroatom-containing, unsaturated or substituted ring systems are 7-azabicyclo[2.2.1]heptane, bicyclo[2.2.2]oct-5-ene and camphor (=1,7,7-trimethyl-2-oxobicyclo[2.2.1]heptane).
Examples of systems from which a tricyclic radical can be derived are twistane (=tricyclo[4.4.0.03,8]decane), adamantane (=tricyclo[3.3.1.13,7]decane), noradamantane (=tricyclo[3.3.1.03,7]nonane), tricyclo[2.2.1.02,6]heptane, tricyclo[5.3.2.04,9]dodecane, tricyclo[5.4.0.02,9]undecane or tricyclo[5.5.1.03,11]tridecane.
Preferably, bicyclic or tricyclic radicals are derived from bridged bicycles or tricycles, i.e., from systems in which rings have two or more than two atoms in common. Additionally preferred, if not stated otherwise, are also bicyclic or tricyclic radicals having 6 to 18 ring members, particularly preferably those having 6 to 14 ring members, very particularly preferably those having 7 to 12 ring members.
Specifically particularly preferred bicyclic and tricyclic radicals are the 2-norbornyl radical, having either the free bond in the exo position or having the free bond in the endo position; the 2-bicyclo[3.2.1]octyl radical; the adamantyl radical; both the 1-adamantyl radical and the 2-adamantyl radical; the homoadamantyl radical and the noradamantyl radical, for example the 3-noradamantyl radical. Additionally preferred are the 1- and the 2-adamantyl radicals.
(C6-C14)-aryl groups are, for example, phenyl, naphthyl, for example 1-naphthyl and 2-naphthyl, biphenylyl, for example 2-biphenylyl, 3-biphenylyl and 4-biphenylyl, anthryl or fluorenyl, (C6-C10)-aryl groups, for example 1-naphthyl, 2-naphthyl and in particular phenyl. Aryl radicals, in particular phenyl radicals, can be monosubstituted or polysubstituted, preferably monosubstituted, disubstituted or trisubstituted, by identical or different radicals from the group consisting of (C1-C8)-alkyl, in particular (C1-C4)-alkyl, (C1-C8)-alkoxy, in particular (C1-C4)-alkoxy, halogen, nitro, amino, trifluoromethyl, hydroxyl, hydroxy-(C1-C4)-alkyl such as, for example, hydroxymethyl or 1-hydroxyethyl or 2-hydroxyethyl, methylenedioxy, ethylenedioxy, formyl, acetyl, cyano, hydroxycarbonyl, aminocarbonyl, (C1-C4)-alkoxycarbonyl, phenyl, phenoxy, benzyl, benzyloxy, tetrazolyl. The same applies, for example to radicals such as arylalkyl or arylcarbonyl. Arylalkyl radicals are, in particular, benzyl and 1- and 2-naphthylmethyl, 2-, 3- and 4-biphenylylmethyl and 9-fluorenylmethyl, which can also be substituted. Substituted arylalkyl radicals are, for example, benzyl radicals and naphthylmethyl radicals substituted in the aryl moiety by one or more (C1-C8)-alkyl radicals, in particular (C1-C4)-alkyl radicals, for example 2-, 3- and 4-methylbenzyl, 4-isobutylbenzyl, 4-tert-butylbenzyl, 4-octylbenzyl, 3,5-dimethylbenzyl, pentamethylbenzyl, 2-, 3-, 4-, 5-, 6-, 7- and 8-methyl-1-naphthylmethyl, 1-, 3-, 4-, 5-, 6-, 7- and 8-methyl-2-naphthylmethyl, benzyl radicals and naphthylmethyl radicals substituted in the aryl moiety by one or more (C1-C8)-alkoxy radicals, in particular (C1-C4)-alkoxy radicals, for example 4-methoxybenzyl, 4-neopentyloxybenzyl, 3,5-dimethoxybenzyl, 3,4-methylenedioxybenzyl, 2,3,4-trimethoxybenzyl, nitrobenzyl radicals, for example 2-, 3- and 4-nitrobenzyl, halobenzyl radicals, for example 2-, 3- and 4-chlorobenzyl and 2-, 3- and 4-fluorobenzyl, 3,4-dichlorobenzyl, pentafluorobenzyl, trifluoromethylbenzyl radicals, for example 3- and 4-trifluoromethylbenzyl or 3,5-bis(trifluoromethyl)benzyl. Substituted arylalkyl radicals, however, can also have different substituents.
In monosubstituted phenyl radicals, the substituent can be located in the 2-, the 3- or the 4-position, the 3- and the 4-position being preferred. If phenyl is disubstituted, the substituents can be in the 1,2-, 1,3- or 1,4-position relative to one another. Disubstituted phenyl can thus be substituted in the 2,3-position, 2,4-position, 2,5-position, the 2,6-position, 3,4-position or the 3,5-position, relative to the linkage site. Preferably, in disubstituted phenyl radicals the two substituents are arranged in the 3-position and the 4-position, relative to the linkage site. In trisubstituted phenyl radicals, the substituents can be present, for example, in the 2,3,4-position, the 2,3,5-position, the 2,4,5-position, the 2,4,6-position, the 2,3,6-position or the 3,4,5-position. The same applies to phenylene radicals, which can be present, for example as 1,4-phenylene or as 1,3-phenylene.
Phenylene-(C1-C3)-alkyl is in particular phenylenemethyl (xe2x80x94C6H4xe2x80x94CH2xe2x80x94) and phenyleneethyl, (C1-C3)-alkylenephenyl in particular methylenephenyl (xe2x80x94CH2xe2x80x94C6H4xe2x80x94). Phenylene-(C2-C6)-alkenyl is in particular phenyleneethenyl and phenylenepropenyl.
Heteroarys include monocyclic or polycyclic aromatic radicals having 5 to 14 ring members, which contains 1, 2, 3, 4 or 5 heteroatoms as ring members. Examples of heteroatoms are N, O and S. If several heteroatoms are contained, these can be identical or different. Heteroaryl radicals can also be monosubstituted or polysubstituted, preferably monosubstituted, disubstituted or trisubstituted, by identical or different radicals selected from the group consisting of (C1-C8)-alkyl, in particular (C1-C4)-alkyl, (C1-C8)-alkoxy, in particular (C1-C4)-alkoxy, halogen, nitro, amino, trifluoromethyl, hydroxyl, hydroxy-(C1-C4)-alkyl such as, for example, hydroxymethyl or 1-hydroxyethyl or 2-hydroxyethyl, methylenedioxy, formyl, acetyl, cyano, hydroxycarbonyl, aminocarbonyl, (C1-C4)-alkoxycarbonyl, phenyl, phenoxy, benzyl, benzyloxy, or tetrazolyl. Preferably heteroaryl is a monocyclic or bicyclic aromatic radical which contains 1, 2, 3 or 4, in particular 1, 2 or 3, identical or different heteroatoms selected from the group consisting of N, O, and S and which can be substituted by 1, 2, 3 or 4, in particular 1, 2 or 3, identical or different substituents selected from the group of (C1-C6)-alkyl, (C1-C6)-alkoxy, fluorine, chlorine, nitro, amino, trifluoromethyl, hydroxyl, hydroxy-(C1-C4)-alkyl, (C1-C4)-alkoxycarbonyl, phenyl, phenoxy, benzyloxy and benzyl. Particularly preferably, heteroaryl is a monocyclic or bicyclic aromatic radical having 5 to 10 ring members, in particular a 5-membered to 6-membered monocyclic aromatic radical which contains 1, 2 or 3, in particular 1 or 2, identical or different heteroatoms selected from the group consisting of N, O, and S and can be substituted by 1 or 2 identical or different substituents selected from the group consisting of (C1-C4)-alkyl, (C1-C4)-alkoxy, phenyl, phenoxy, benzyloxy, and benzyl.
Heterocycles representing monocyclic or bicyclic 5-membered to 12-membered heterocyclic rings can be aromatic or partially or completely saturated. They can be unsubstituted or substituted on one or more carbon atoms or on one or more nitrogen atoms by identical or different substituents, such as is indicated for the radical heteroaryl. In particular, the heterocyclic ring can be monosubstituted or polysubstituted on carbon atoms by identical or different radicals selected from the group consisting of (C1-C8)-alkyl, for example (C1-C4)-alkyl, (C1-C8)-alkoxy, for example (C1-C4)-alkoxy such as methoxy, phenyl-(C1-C4)-alkoxy, for example benzyloxy, hydroxyl, oxo, halogen, nitro, amino or trifluoromethyl, and/or ring nitrogen atoms in heterocyclic rings and in heteroaryl radicals can be substituted by (C1-C8)-alkyl, for example (C1-C4)-alkyl such as methyl or ethyl, or by optionally substituted phenyl or phenyl-(C1-C4)-alkyl, for example, benzyl.
Examples of heterocycles on which the heteroaryl radical or the radical of the monocyclic or bicyclic 5-membered to 12-membered heterocyclic ring can be based are pyrrole, furan, thiophene, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole, tetrazole, pyridine, pyrazine, pyrimidine, indole, isoindole, indazole, phthalazine, quinoline, isoquinoline, quinoxaline, quinazoline, cinnoline, xcex2-carboline or benzo-fused, cyclopenta-fused, cyclohexa-fused or cyclohepta-fused derivatives of these heterocycles.
Nitrogen heterocycles can also be present as N-oxides.
Radicals which can be heteroaryl or the radical of a monocyclic or bicyclic 5-membered to 12-membered heterocyclic ring are, for example, 2- or 3-pyrrolyl, phenylpyrrolyl, for example 4- or 5-phenyl-2-pyrrolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 4-imidazolyl, methylimidazolyl, for example 1-methyl-2-, -4- or -5-imidazolyl, 1,3-thiazol-2-yl, 2-pyridyl, 3-pyridyl, 4-pyridyl, N-oxido-2-, -3- or -4-pyridyl, 2-pyrazinyl, 2-, 4- or 5-pyrimidinyl, 2-, 3- or 5-indolyl, substituted 2-indolyl, for example 1-methyl-, 5-methyl-, 5-methoxy-, 5-benzyloxy-, 5-chloro- or 4,5-dimethyl-2-indolyl, 1-benzyl-2- or -3-indolyl, 4,5,6,7-tetrahydro-2-indolyl, cyclohepta[b]-5-pyrrolyl, 2-, 3- or 4-quinolyl, 1-, 3- or 4-isoquinolyl, 1-oxo-1,2-dihydro-3-isoquinolyl, 2-quinoxalinyl, 2-benzofuranyl, 2-benzothienyl, 2-benzoxazolyl or 2-benzothiazolyl or, as radicals of partially hydrogenated or completely hydrogenated heterocyclic rings, for example also dihydropyridinyl, pyrrolidinyl, for example 2- or 3-(N-methylpyrrolidinyl), piperazinyl, morpholinyl, thiomorpholinyl, tetrahydrothienyl, benzodioxolanyl.
Heterocyclic radicals representing the radical Het can be unsubstituted on carbon atoms and/or ring nitrogen atoms or monosubstituted or polysubstituted, for example disubstituted, trisubstituted, tetrasubstituted or pentasubstituted, by identical or different substituents. Carbon atoms can be substituted, for example, by (C1-C8)-alkyl, in particular (C1-C4)-alkyl, (C1-C8)-alkoxy, in particular (C1-C4)-alkoxy, halogen, nitro, amino, trifluoromethyl, hydroxyl, oxo, cyano, hydroxycarbonyl, aminocarbonyl, (C1-C4)-alkoxycarbonyl, phenyl, phenoxy, benzyl, benzyloxy, tetrazolyl, in particular by (C1-C4)-alkyl, for example methyl, ethyl or tert-butyl, (C1-C4)-alkoxy, for example methoxy, hydroxyl, oxo, phenyl, phenoxy, benzyl, benzyloxy. Sulfur atoms can be oxidized to the sulfoxide or to the sulfone. Examples of the radical Het are 1-pyrrolidinyl, 1-piperidinyl, 1-piperazinyl, 4-substituted 1-piperazinyl, 4-morpholinyl, 4-thiomorpholinyl, 1-oxo-4-thiomorpholinyl, 1,1-dioxo-4-thiomorpholinyl, perhydroazepin-1-yl, 2,6-dimethyl-1-piperidinyl, 3,3-dimethyl-4-morpholinyl, 4-isopropyl-2,2,6,6-tetramethyl-1-piperazinyl, 4-acetyl-1-piperazinyl, and 4-ethoxycarbonyl-1-piperazinyl.
The heteroaromatic radicals furyl, thienyl, pyrrolyl, imidazolyl and pyridyl representing R1 can be bonded via any of the carbon atoms, thus the radicals 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyrrolyl, 3-pyrrolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 2-pyridyl, 3-pyridyl and 4-pyridyl can be present. The phenyl radical representing R1 and the heteroaromatic radicals can also be benzo-fused, R1 can thus also be naphthyl, benzo[b]furyl (=benzofuryl), benzo[c]furyl, benzo[b]thienyl (=benzothienyl), benzo[c]thienyl, indolyl, benzimidazolyl, quinolyl and isoquinolyl, in particular naphthyl, benzofuryl, benzothienyl, indolyl, benzimidazolyl, quinolyl and isoquinolyl. The benzo-fused radicals representing R1 are preferably bonded via a carbon atom in the heterocyclic ring, where they can be bonded in turn via each of these carbon atoms. Examples of such benzo-fused radicals representing R1 are 1-naphthyl, 2-naphthyl, 2-benzofuryl, 3-benzofuryl, 2-benzothienyl, 3-benzothienyl, 2-indolyl, 3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl, 7-indolyl, 2-benzimidazolyl, 2-quinolyl, 3-quinolyl, 4-quinolyl, 1-isoquinolyl, 3-isoquinolyl or 4-isoquinolyl.
The radicals representing R1 can be unsubstituted or can be substituted in any desired positions by one or more, for example one, two, three or four, identical or different substituents. The above explanations, for example with respect to the substituent positions in phenyl radicals and heterocyclic radicals, correspondingly also apply to the radicals representing R1. Suitable substituents on carbon atoms are thus, for example, (C1-C8)-alkyl, in particular (C1-C4)-alkyl, (C1-C8)-alkoxy, in particular (C1-C4)-alkoxy, halogen, nitro, amino, trifluoromethyl, hydroxyl, hydroxy-(C1-C4)-alkyl such as hydroxymethyl or 1-hydroxyethyl or 2-hydroxyethyl, methylenedioxy, ethylenedioxy, cyano, formyl, acetyl, hydroxycarbonyl, aminocarbonyl, (C1-C4)-alkoxycarbonyl, phenyl, phenoxy, benzyl, benzyloxy and tetrazolyl, where these substituents can be on carbon atoms in the heterocyclic ring and/or on carbon atoms in a fused benzene ring. Nitrogen atoms in pyrrolyl radicals, imidazolyl radicals and their benzo-fused analogs can be unsubstituted or, in particular, can be substituted, for example, by (C1-C8)-alkyl, for example (C1-C4)-alkyl such as methyl or ethyl, by optionally substituted phenyl or phenyl-(C1-C4)-alkyl, for example benzyl, or, for example, by (C1-C4)-alkyl-CO.
The substituent on a substituted alkylene radical representing B can on the one hand contain a cycle when it is a substituent selected from the group consisting of (C3-C10)-cycloalkyl, (C3-C10)-cycloalkyl-(C1-C6)-alkyl, optionally substituted (C6-C14)-aryl, (C6-C14)-aryl-(C1-C6)-alkyl optionally substituted in the aryl radical, optionally substituted heteroaryl and heteroaryl-(C1-C6) optionally substituted in the heteroaryl radical, and on the other hand it can be acyclic if it is a substituent from the group consisting of (C1-C8)-alkyl, (C2-C8)-alkenyl and (C2-C8)-alkynyl. The acyclic substituents can contain 2, 3, 4, 5, 6, 7 or 8 carbon atoms or, in the case of the saturated alkyl radical, also 1 carbon atom. In the case of the alkenyl radicals and alkynyl radicals, the double bond or triple bond can be located in any desired position and in the case of the double bond can have the cis configuration or trans configuration. As explained above, these alkyl radicals, alkenyl radicals, and alkynyl radicals can be straight-chain or branched.
Examples of substituents on the (C1-C6)-alkylene radical representing B are methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, isopropyl, isobutyl, isopentyl, isohexyl, sec-butyl, tert-butyl, tert-pentyl, neopentyl, neohexyl, 3-methylpentyl, 2-ethylbutyl, vinyl, allyl, 1-propenyl, 2-butenyl, 3-butenyl, 3-methyl-2-butenyl, ethynyl, 1-propynyl, 2-propynyl, 6-hexynyl, phenyl, benzyl, 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl, 4-biphenylylmethyl, cyclopropyl, cyclopropylmethyl, cyclopentyl, cyclohexyl, cyclohexylmethyl, 2-cyclohexylethyl, 3-cyclooctylpropyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 4-pyridylmethyl, 2-(4-pyridyl)ethyl, 2-furylmethyl, 2-thienylmethyl, 3-thienylmethyl or 2-(3-indolyl)ethyl.
Halogen is fluorine, chlorine, bromine or iodine, in particular fluorine or chlorine.
The radical of an amino acid, imino acid or azaamino acid or of a dipeptide is obtained from the corresponding amino acid, imino acid or azaamino acid or the dipeptide as customary in peptide chemistry by formally removing a hydrogen atom from the N-terminal amino group or from the imino group. By means of the free bond on the amino group or the imino group thus formed this group is then linked in peptide fashion through an amide bond to the CO group in the group R6xe2x80x94CO.
The natural and unnatural amino acids can be present in all stereochemical forms, for example in the D form, the L form or in the form of a mixture of stereoisomers, for example in the form of a racemate. Preferred amino acids are xcex1-amino acids and xcex2-amino acids; xcex1-amino acids are particularly preferred. Suitable amino acids which may be mentioned, for example, are (cf. Houben-Weyl, Methoden der organischen Chemie [Methods of Organic Chemistry], Volume 15/1 and 15/2, Georg Thieme Verlag, Stuttgart, 1974):
Aad, Abu, xcex3Abu, ABz, 2ABz, xcex5Aca, Ach, Acp, Adpd, Ahb, Aib, xcex2Aib, Ala, xcex2Ala, xcex94Ala, Alg, All, Ama, Amt, Ape, Apm, Apr, Arg, Asn, Asp, Asu, Aze, Azi, Bai, Bph, Can, Cit, Cys, (Cys)2, Cyta, Daad, Dab, Dadd, Dap, Dapm, Dasu, Djen, Dpa, Dtc, Fel, Gln, Glu, Gly, Guv, hAla, hArg, hCys, hGln, hGlu, His, hlle, hLeu, hLys, hMet, hphe, hPro, hSer, hThr, hTrp, hTyr, Hyl, Hyp, 3Hyp, Ile, Ise, Iva, Kyn, Lant, Lcn, Leu, Lsg, Lys, xcex2Lys, xcex94Lys, Met, Mim, Min, nArg, Nle, Nva, Oly, Orn, Pan, Pec, Pen, Phe, Phg, Pic, Pro, xcex94Pro, Pse, Pya, Pyr, Pza, Qin, Ros, Sar, Sec, Sem, Ser, Thi, xcex2Thi, Thr, Thy, Thx, Tia, Tle, Tly, Trp, Trta, Tyr, Val, tert-butylglycine (Tbg), -neopentylglycine (Npg), cyclohexylglycine (Chg), cyclohexylalanine (Cha), 2-thienylalanine (Thia), 2,2-diphenylaminoacetic acid, 2-(p-tolyl)-2-phenylaminoacetic acid, and 2-(p-chlorophenyl)-aminoacetic acid.
If R6 is the radical of a natural or unnatural xcex1-amino acid which is not branched on the xcex1-carbon atom, i.e., which carries a hydrogen atom on the xcex1-carbon atom, then the radical xe2x80x94N(Rb)xe2x80x94CH(SC)xe2x80x94COxe2x80x94L is present in which COxe2x80x94L is the acid group of the amino acid or a derivative thereof, for example an ester group or an amide group, Rb is for example hydrogen and SC is the side chain of the xcex1-amino acid, i.e., for example, one of the substituents which are contained in the xcex1-position of the above-mentioned xcex1-amino acids which are unbranched in the xcex1-position. Examples of side chains are alkyl radicals, for example the methyl group in alanine or the isopropyl group in valine, the benzyl radical in phenylalanine, the phenyl radical in phenylglycine, the 4-aminobutyl radical in lysine or the hydroxy-carbonyl methyl group in aspartic acid. Apart from arrangement by chemical structure, such side chains, and thus the amino acids, can also be arranged in groups within the meaning of the present invention on the basis of their physicochemical properties, for example lipophilic side chains can be differentiated from hydrophilic side chains which contain polar groups. Examples of lipophilic side chains which can be contained in amino acids representing R6 are alkyl radicals, arylalkyl radicals or aryl radicals.
Azaamino acids are natural or unnatural amino acids in which a CH unit is replaced by a nitrogen atom. For example, in xcex1-amino acids the central structural unit 
Suitable radicals of imino acids are, in particular, radicals of heterocycles selected from the following group: pyrrolidine-2-carboxylic acid; piperidine-2-carboxylic acid; 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid; decahydroisoquinoline-3-carboxylic acid; octahydroindole-2-carboxylic acid; decahydroquinoline-2-carboxylic acid; octahydrocyclopenta[b]pyrrole-2-carboxylic acid; 2-azabicyclo[2.2.2]octane-3-carboxylic acid; 2-azabicyclo[2.2.1]heptane-3-carboxylic acid; 2-azabicyclo[3.1.0]hexane-3-carboxylic acid; 2-azaspiro[4.4]nonane-3-carboxylic acid; 2-azaspiro[4.5]decane-3-carboxylic acid; spiro(bicyclo[2.2.1]heptane)-2,3-pyrrolidine-5-carboxylic acid; spiro(bicyclo[2.2.2]octane)-2,3-pyrrolidine-5-carboxylic acid; 2-azatricyclo[4.3.0.16,9]decane-3-carboxylic acid; decahydrocyclohepta[b]pyrrole-2-carboxylic acid; decahydrocycloocta[c]pyrrole-2-carboxylic acid; octahydrocyclopenta[c]pyrrole-2-carboxylic acid; octahydroisoindole-1-carboxylic acid; 2,3,3a ,4,6a-hexahydrocyclopenta[b]pyrrole-2-carboxylic acid; 2,3,3a,4,5,7a-hexahydroindole-2-carboxylic acid; tetrahydrothiazole-4-carboxylic acid; isoxazolidine-3-carboxylic acid; pyrazolidine-3-carboxylic acid, and hydroxypyrrolidine-2-carboxylic acid, all of which can optionally be substituted (see following formulae): 
The heterocycles on which the radicals mentioned above are based are disclosed, for example, in U.S. Pat. Nos. 4,344,949; 4,374,847; 4,350,704; EP-A 29,486; EP-A 31,741; EP-A 46,953; EP-A 49,605; EP-A 49,658; EP-A 50,800; EP-A 51,020; EP-A 52,870; EP-A 79,022; EP-A 84,164; EP-A 89,637; EP-A 90,341; EP-A 90,362; EP-A 105,102; EP-A 109,020; EP-A 111,873; EP-A 271,865; and EP-A 344,682
Dipeptides can contain natural or unnatural amino acids, imino acids and azaamino acids as structural units. In addition, the natural or unnatural amino acids, imino acids, azaamino acids and dipeptides can also be present in the form of derivatives of the carboxylic acid group, for example as esters or amides, such as, for example, as methyl esters, ethyl esters, n-propyl esters, isopropyl esters, isobutyl esters, tert-butyl esters, benzyl esters, unsubstituted amides, methylamides, ethylamides, semicarbazides or xcfx89-amino-(C2-C8)-alkylamides.
Functional groups in radicals of amino acids, imino acids, azaamino acids and dipeptides as well as in other parts of the molecules of the formula I can be present in protected form. Suitable protective groups such as, for example, urethane protective groups, carboxyl protective groups and side chain protective groups are described in Hubbuch, Kontakte (Merck) 1979, No. 3, pages 14 to 23, and in Bxc3xcllesbach, Kontakte (Merck) 1980, No. 1, pages 23 to 35. The following may be mentioned in particular: Aloc, Pyoc, Fmoc, Tcboc, Z, Boc, Ddz, Bpoc, Adoc, Msc, Moc, Z(NO2), Z(Haln), Bobz, Iboc, Adpoc, Mboc, Acm, tert-butyl, OBzl, ONbzl, OMbzl, Bzl, Mob, Pic, Trt.
Physiologically tolerable salts of the compounds of the formula I are in particular pharmaceutically utilizable or nontoxic salts. In the case of compounds of the formula I which contain acidic groups, for example carboxylic acid groups, such salts are, for example, alkali metal salts or alkaline earth metal salts as well as salts with ammonia and physiologically tolerable organic amines. Such compounds of the formula I can thus be present, for example, as sodium salts, potassium salts, calcium salts, magnesium salts or as acid addition salts with amines such as, for example, triethylamine, ethanolamine, tris(2-hydroxyethyl)amine or amino acids, in particular basic amino acids.
Compounds of the formula I which contain basic groups, for example an amino group or a guanidino group, form salts with inorganic acids, such as, for example, hydrochloric acid, sulfuric acid or phosphoric acid, and with organic carboxylic acids or sulfonic acids, such as, for example, acetic acid, citric acid, benzoic acid, maleic acid, fumaric acid, tartaric acid, methanesulfonic acid or p-toluenesulfonic acid. If the compounds of the formula I simultaneously contain acidic and basic groups in the molecule, the invention also includes internal salts or betaines in addition to the salt forms described.
Salts can be obtained from the compounds of the formula I according to customary procedures known to the person skilled in the art, for example by combining with an organic or inorganic acid or base in a solvent or dispersant, or alternatively from other salts by anion exchange or cation exchange. The present invention also includes all salts of the compounds of the formula I which are not directly suitable for use in pharmaceuticals because of low physiological tolerability, but are suitable, for example, as intermediates for chemical reactions or for the preparation of physiologically tolerable salts.
The compounds of the formula I can be present in stereoisomeric forms. If the compounds of the formula I contain one or more centers of asymmetry, these can independently of one another have the S configuration or the R configuration. The invention includes all possible stereoisomers, for example enantiomers and diastereomers, and mixtures of two or more stereoisomeric forms, for example mixtures of enantiomers and/or diastereomers, in all ratios. The invention thus relates to enantiomers in enantiomerically pure form, both as levorotatory and dextrorotatory antipodes, in the form of racemates and in the form of mixtures of the two enantiomers in all ratios. In the presence of cis/trans isomerism, the invention relates to both the cis form and the trans form and mixtures of these forms. Individual stereoisomers can be prepared, if desired, by separation of a mixture according to customary methods, for example by chromatography or crystallization, by use of stereochemically homogeneous starting substances in the synthesis or by stereoselective synthesis. If appropriate, derivatization can be carried out before separation of stereoisomers. A stereoisomer mixture can be separated at the stage of the compounds of the formula I or at the stage of a starting substance or of an intermediate in the course of the synthesis.
The compounds of the formula I according to the invention can moreover contain mobile hydrogen atoms, i.e., be present in various tautomeric forms. The present invention also relates to all these tautomers. The present invention furthermore includes all solvates of compounds of the formula I, for example hydrates or adducts with alcohols, as well as derivatives of the compounds of the formula I, for example esters, prodrugs and active metabolites.
The individual structural elements in the formula I preferably independently of one another have the following meanings.
W is preferably R1xe2x80x94Axe2x80x94C(R13).
Z is preferably oxygen.
A is preferably a direct bond or methylene, particularly preferably a direct bond.
B is preferably a divalent radical selected from the group consisting of methylene, ethylene, trimethylene, tetramethylene, vinylene, phenylene or a substituted (C1-C4)-alkylene radical. Particularly preferably, B is a divalent methylene radical or ethylene radical (=1,2-ethylene), in particular a methylene radical, where each of these radicals can be unsubstituted or substituted. Very particularly preferably, B is a substituted methylene radical or ethylene radical, in particular a substituted methylene radical. If a divalent alkylene radical representing B, in particular a methylene radical or ethylene radical (=1,2-ethylene), is substituted, it is preferably substituted by a radical selected from the group consisting of (C1-C8)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl, (C3-C7)-cycloalkyl, in particular (C5-C6)-cycloalkyl, (C3-C7)-cycloalkyl-(C1-C4)-alkyl, in particular (C5-C6)-cycloalkyl-(C1-C4)-alkyl, optionally substituted (C6-C10)-aryl, (C6-C10)-aryl-(C1-C4)-alkyl optionally substituted in the aryl radical, optionally substituted heteroaryl and heteroaryl-(C1-C4)-alkyl optionally substituted in the heteroaryl radical. Particularly preferably, a substituted alkylene radical representing B is substituted by (C1-C8)-alkyl, i.e., by a straight-chain or branched alkyl radical having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms.
E is preferably tetrazolyl or R10CO, particularly preferably R10CO.
R is preferably hydrogen, (C1-C8)-alkyl or benzyl, particularly preferably hydrogen or (C1-C8)-alkyl, very particularly preferably hydrogen or (C1-C4)-alkyl, in particular hydrogen, methyl or ethyl.
R0 is preferably (C1-C8)-alkyl, (C3-C12)-cycloalkyl, (C3-C12)-cycloalkyl-(C1-C8)-alkyl, (C6-C12)-bicycloalkyl, (C6-C12)-bicycloalkyl-(C1-C8)-alkyl, (C6-C12)-tricycloalkyl, (C6-C12)-tricycloalkyl-(C1-C8)-alkyl, optionally substituted (C6-C14)-aryl, (C6-C14)-aryl-(C1-C8)-alkyl optionally substituted in the aryl radical, optionally substituted heteroaryl or heteroaryl-(C1-C8)-alkyl optionally substituted in the heteroaryl radical, particularly preferably (C1-C8)-alkyl, (C3-C12)-cycloalkyl, (C3-C12)-cycloalkyl-(C1-C4)-alkyl, optionally substituted (C6-C14)-aryl, (C6-C14)-aryl-(C1-C4)-alkyl optionally substituted in the aryl radical, optionally substituted heteroaryl or heteroaryl-(C1-C4)-alkyl optionally substituted in the heteroaryl radical, very particularly preferably optionally substituted (C6-C14)-aryl, (C6-C14)-aryl-(C1-C4)-alkyl optionally substituted in the aryl radical, optionally substituted heteroaryl or heteroaryl-(C1-C4)-alkyl optionally substituted in the heteroaryl radical, moreover preferably (C6-C14)-aryl-(C1-C4)-alkyl optionally substituted in the aryl radical or heteroaryl-(C1-C4)-alkyl substituted in the heteroaryl radical. It is especially preferred if R0 is (C6-C14)-aryl-(C1-C4)-alkyl optionally substituted in the aryl radical, in particular biphenylylmethyl, naphthylmethyl or benzyl which is unsubstituted or monosubstituted or polysubstituted in the aryl radical.
R1 is preferably a radical selected from the group consisting of phenyl, furyl, thienyl, pyrrolyl, imidazolyl and pyridyl, which is not benzo-fused. Particularly preferably, R1 is a phenyl radical, a 2-furyl radical, a 3-furyl radical, a 2-thienyl radical, a 3-thienyl radical, a 3-pyrrolyl radical, a 4-imidazolyl radical, a 3-pyridyl radical or a 4-pyridyl radical, very particularly preferably a phenyl radical, a 2-furyl radical, a 3-furyl radical, a 2-thienyl radical, a 3-thienyl radical, a 4-imidazolyl radical or a 4-pyridyl radical, moreover preferably a phenyl radical or a 4-pyridyl radical. Preferably, a radical representing R1 is unsubstituted or substituted by one, two or three, in particular by one or by two, identical or different radicals of the type which are indicated above as suitable substituents on carbon atoms and nitrogen atoms in R1. Particularly preferably, a radical representing R1 is unsubstituted. Preferred substituents on carbon atoms in the radical R1 are (C1-C4)-alkyl, (C1-C4)-alkoxy, halogen, amino, trifluoromethyl, hydroxyl, hydroxy-(C1-C4)-alkyl, methylenedioxy, ethylenedioxy, phenyl, phenoxy, benzyl and benzyloxy, in particular as substituents on carbon atoms of a heteroaryl radical representing R1. Particularly preferred substituents on carbon atoms in R1, in particular on carbon atoms of a phenyl radical representing R1, are (C1-C4)-alkyl, (C1-C4)-alkoxy, halogen, trifluoromethyl, hydroxyl, hydroxy-(C1-C4)-alkyl, methylenedioxy, ethylenedioxy, phenyl, phenoxy, benzyl and benzyloxy.
R2 is preferably hydrogen or (C1-C8)-alkyl, particularly preferably hydrogen or (C1-C4)-alkyl.
R3 is preferably (C1-C8)-alkyl, optionally substituted (C6-C14)-aryl, (C6-C14)-aryl-(C1-C4)-alkyl optionally substituted in the aryl radical, (C3-C8)-cycloalkyl, (C3-C8)-cycloalkyl-(C1-C4)-alkyl, (C6-C12)-bicycloalkyl, (C6-C12)-bicycloalkyl-(C1-C4)-alkyl, (C6-C12)-tricycloalkyl, (C6-C12)-tricycloalkyl-(C1-C4)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl, optionally substituted heteroaryl, heteroaryl-(C1-C4)-alkyl optionally substituted in the heteroaryl radical, R11NH, CON(CH3)R4, CONHR4, CON(CH3)R15 or CONHR15, particularly preferably optionally substituted (C6-C14)-aryl, in particular optionally substituted (C6-C10)-aryl, optionally substituted 5-membered or 6-membered heteroaryl having one or two identical or different heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, in particular pyridyl, R11NH, CON(CH3)R4, CONHR4, CON(CH3)R15 or CONHR15, very particularly preferably optionally substituted (C6-C10)-aryl, R11NH, CON(CH3)R4, CONHR4, CON(CH3)R15 or CONHR15.
R4 is preferably (C1-C8)-alkyl which can optionally be substituted as indicated above in the definition of R4, particularly preferably (C1-C8)-alkyl, in particular (C1-C6)-alkyl, which is substituted by one or two of the substituents indicated in the above definition of R4. It is very particularly preferred if one of the substituents is bonded in the 1-position of the alkyl group, i.e., to that carbon atom of the alkyl group to which the nitrogen atom in the group CONHR4 or in the group CON(CH3)R4 is also bonded, and if this substituent in the 1-position is one of the radicals hydroxycarbonyl, aminocarbonyl, mono- or di-((C1-C18)-alkyl)-aminocarbonyl, (C6-C14)-aryl-(C1-C8)-alkoxycarbonyl which can also be substituted in the aryl radical, Het-CO, R6xe2x80x94CO, (C1-C8)-alkoxycarbonyl or tetrazolyl. In this very particularly preferred case, the radical xe2x80x94NHR4 or the radical xe2x80x94N(CH3)R4 is thus the radical of an xcex1-amino acid or of an N-methyl-xcex1-amino acid or of a derivative thereof, where this radical is formally obtained by abstraction of a hydrogen atom from the amino group of the amino acid. Especially preferred xcex1-amino acids are in this case those having a lipophilic side chain, for example phenylglycine, phenylalanine, valine, leucine, isoleucine and homologs thereof, as well as derivatives of these amino acids such as esters, amides or the derivatives in which the carboxylic acid group is converted into the radical Het-CO.
R11 is preferably hydrogen, R12a, R12axe2x80x94CO, Hxe2x80x94CO, R12axe2x80x94Oxe2x80x94CO, R12bxe2x80x94CO, R12bxe2x80x94CS or R12axe2x80x94S(O)2, particularly preferably hydrogen, R12a, R12axe2x80x94CO, R12axe2x80x94Oxe2x80x94CO, R12bxe2x80x94CO, R12bxe2x80x94CS or R12axe2x80x94S(O)2, very particularly preferably R12a, R12axe2x80x94CO, R12axe2x80x94Oxe2x80x94CO, R12bxe2x80x94CO, R12bxe2x80x94CS or R12axe2x80x94S(O)2, moreover preferably R12a, R12axe2x80x94CO, R12axe2x80x94Oxe2x80x94CO, R12bxe2x80x94CO or R12axe2x80x94S(O)2.
R12a is preferably (C1-C10)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl, (C3-C12)-cycloalkyl, (C3-C12)-cycloalkyl-(C1-C8)-alkyl, optionally substituted (C6-C14)-aryl, (C6-C14)-aryl-(C1-C8)-alkyl optionally substituted in the aryl radical, optionally substituted heteroaryl, heteroaryl-(C1-C8)-alkyl optionally substituted in the heteroaryl radical, or the radical R15.
R12b is preferably R12axe2x80x94NH.
R13 is preferably hydrogen, (C1-C6)-alkyl, (C3-C8)-cycloalkyl or benzyl, particularly preferably hydrogen or (C1-C6)-alkyl, very particularly preferably hydrogen or (C1-C4)-alkyl, in particular (C1-C4)-alkyl, where a preferred alkyl radical representing R13 is the methyl radical.
R15 is preferably R16xe2x80x94(C1-C3)-alkyl or R16, particularly preferably R16xe2x80x94(C1)-alkyl or R16. Additionally preferably, R15, if R3 is COOR15, is the exo-2-norbornyl radical, the endo-2-norbornyl radical or the bicyclo[3.2.1]octyl radical, and R15, if R3 is CONHR15, is the exo-2-norbornyl radical, the endo-2-norbornyl radical, the 3-noradamantyl radical and in particular the 1-adamantyl radical, the 2-adamantyl radical, the 1-adamantylmethyl radical or the 2-adamantylmethyl radical.
R16 is preferably a 6-membered to 14-membered, in particular 7-membered to 12-membered, bridged bicyclic or tricyclic radical which is saturated or partially unsaturated and which can also contain one to four, in particular one, two or three, especially one or two, identical or different heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur and which can also be substituted by one or more identical or different substituents selected from the group consisting of (C1-C4)-alkyl and oxo.
Het is preferably the radical of a 5-membered to 10-membered, saturated monocyclic or polycyclic heterocycle bonded via a ring nitrogen atom, which can contain one or two identical or different additional ring heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur and can be optionally substituted on carbon atoms and on ring nitrogen atoms, where substituents on additional ring nitrogen atoms can be identical or different radicals selected from the group consisting of hydrogen, Rh, HCO, RhCO or RhOxe2x80x94CO. Particularly preferably, Het is a heterocycle of this type which contains no additional ring heteroatom or which contains one additional ring heteroatom selected from the group consisting of nitrogen, oxygen and sulfur, very particularly preferably Het is the radical of a 5-membered, 6-membered or 7-membered, saturated monocyclic heterocycle bonded via a nitrogen atom, which contains no additional ring heteroatom or which contains one additional ring heteroatom from the group consisting of nitrogen, oxygen and sulfur, where also in these cases the radical Het can be unsubstituted or can be substituted on carbon atoms and/or on additional ring nitrogen atoms.
If R3 is one of the radicals (C1-C8)-alkyl, optionally substituted (C6-C14)-aryl, (C6-C14)-aryl-(C1-C8)-alkyl optionally substituted in the aryl radical, optionally substituted heteroaryl, heteroaryl-(C1-C8)-alkyl optionally substituted in the heteroaryl radical, (C3-C8)-cycloalkyl, (C3-C8)-cycloalkyl-(C1-C8)-alkyl, (C6-C12)-bicycloalkyl, (C6-C12)-bicycloalkyl-(C1-C8)-alkyl, (C6-C12)-tricycloalkyl, (C6-C12)-tricycloalkyl-(C1-C8)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl, CON(CH3)R4, CONHR4, COOR15, CON(CH3)R15 or CONHR15, e is preferably 0 and h is preferably 1. If R3 is R11NH, e is preferably 1 and h is preferably 0.
Preferred compounds of the formula I are those compounds in which one or more of the radicals have preferred meanings, all combinations of preferred substituent meanings being a subject of the present invention. Particularly preferred compounds of the formula I are those in which, simultaneously
W is R1xe2x80x94Axe2x80x94C(R13);
Z is oxygen or sulfur;
A is a direct bond or methylene;
B is a divalent methylene radical or ethylene radical, both of which can be unsubstituted or can be substituted by a radical selected from the group consisting of (C1-C8)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl, (C3-C10)-cycloalkyl, (C3-C10)-cycloalkyl-(C1-C6)-alkyl, optionally substituted (C6-C14)-aryl, (C1-C14)-aryl-(C1-C6)-alkyl optionally substituted in the aryl radical, optionally substituted heteroaryl and heteroaryl-(C1-C6)-alkyl optionally substituted in the heteroaryl radical;
E is tetrazolyl or R10CO;
R is hydrogen or (C1-C8)-alkyl;
R0 is hydrogen, (C1-C8)-alkyl, (C3-C12)-cycloalkyl, (C3-C12)-cycloalkyl-(C1-C8)-alkyl, (C6-C12)-bicycloalkyl, (C6-C12)-bicycloalkyl-(C1-C8)-alkyl, (C6-C12)-tricycloalkyl, (C6-C12)-tricycloalkyl-(C1-C8)-alkyl, optionally substituted (C6-C14)-aryl, (C6-C14)-aryl-(C1-C8)-alkyl optionally substituted in the aryl radical, optionally substituted heteroaryl, heteroaryl-(C1-C8)-alkyl optionally substituted in the heteroaryl radical, Hxe2x80x94CO, (C1-C8)-alkyl-CO, (C3-C12)-cycloalkyl-CO, (C3-C12)-cycloalkyl-(C1-C8)-alkyl-CO, (C6-C12)-bicycloalkyl-CO, (C6-C12)-bicycloalkyl-(C1-C8)-alkyl-CO, (C6-C12)-tricycloalkyl-CO, (C6-C12)-tricycloalkyl-(C1-C8)-alkyl-CO, optionally substituted (C6-C14)-aryl-CO, (C6-C14)-aryl-(C1-C8)-alkyl-CO optionally substituted in the aryl radical, optionally substituted heteroaryl-CO, heteroaryl-(C1-C8)-alkyl-CO optionally substituted in the heteroaryl radical, (C1-C8)-alkyl-S(O)n, (C3-C12)-cycloalkyl-S(O)n, (C3-C12)-cycloalkyl-(C1-C8)-alkyl-S(O)n, (C6-C12)-bicycloalkyl-S(O)n, (C6-C12)-tricycloalkyl-(C1-C8)-alkyl-S(O)n, optionally substituted (C6-C14)-aryl-S(O)n, (C6-C14)-aryl-(C1-C8)-alkyl-S(O), optionally substituted in the aryl radical, optionally substituted heteroaryl-S(O)n or heteroaryl-(C1-C8)-alkyl-S(O)n optionally substituted in the heteroaryl radical, where n is 1 or 2;
R1 is an optionally substituted radical selected from the group of phenyl, furyl, thienyl, pyrrolyl, imidazolyl and pyridyl, where each of these radicals can also be benzo-fused;
R2 is hydrogen or (C1-C8)-alkyl;
R3 is hydrogen, (C1-C8)-alkyl, optionally substituted (C6-C14)-aryl, (C6-C14)-aryl-(C1-C8)-alkyl optionally substituted in the aryl radical, optionally substituted heteroaryl, heteroaryl-(C1-C8)-alkyl optionally substituted in the heteroaryl radical, (C3-C8)-cycloalkyl, (C3-C8)-cycloalkyl-(C1-C8)-alkyl, (C6-C12)-bicycloalkyl, (C6-C12)-bicycloalkyl-(C1-C8)-alkyl, (C6-C12)-tricycloalkyl, (C6-C12)-tricycloalkyl-(C1-C8)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl, R11NH, CON(CH3)R4, CONHR4, COOR15, CON(CH3)R15 or CONHR15;
R4 is (C1-C8)-alkyl which can optionally be monosubstituted or polysubstituted by identical or different radicals selected from the group consisting of hydroxyl, (C1-C8)-alkoxy, R5, optionally substituted (C3-C8)-cycloalkyl, hydroxycarbonyl, aminocarbonyl, mono- or di-((C1-C18)-alkyl)-aminocarbonyl, (C6-C14)-aryl-(C1-C8)-alkoxycarbonyl, which can also be substituted in the aryl radical, (C1-C8)-alkoxycarbonyl, Het-CO, R6xe2x80x94CO, tetrazolyl and trifluoromethyl;
R5 is optionally substituted (C6-C14)-aryl, (C6-C14)-aryl-(C1-C8)-alkyl optionally substituted in the aryl radical or an optionally substituted monocyclic or bicyclic 5-membered to 12-membered heterocyclic ring, which can be aromatic, partially hydrogenated or completely hydrogenated and which can contain one, two or three identical or different heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur;
R6 is the radical of a natural or unnatural amino acid, imino acid, optionally Nxe2x80x94(C1-C8)-alkylated or Nxe2x80x94((C6-C14)-aryl-(C1-C8)-alkylated) azaamino acid which can also be substituted in the aryl radical, or the radical of a dipeptide, as well as their esters and amides, where free functional groups can be protected by protective groups customary in peptide chemistry;
R10 is hydroxyl, (C1-C18)-alkoxy, (C6-C14)-aryl-(C1-C8)-alkoxy which can also be substituted in the aryl radical, optionally substituted (C6-C14)-aryloxy, (C1-C8)-alkylcarbonyloxy-(C1-C6)-alkoxy, (C6-C14)-arylcarbonyloxy-(C1-C6)-alkoxy, amino or mono- or di-((C1-C18)-alkyl)-amino;
R11 is hydrogen, R12a, R12axe2x80x94CO, R12axe2x80x94Oxe2x80x94CO, R12bxe2x80x94CO, R12bxe2x80x94CS or R12axe2x80x94S(O)2;
R12a is (C1-C18)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl, (C3-C12)-cycloalkyl, (C3-C12)-cycloalkyl-(C1-C8)-alkyl, optionally substituted (C6-C14)-aryl, (C6-C14)-aryl-(C1-C8)-alkyl optionally substituted in the aryl radical, optionally substituted heteroaryl, heteroaryl-(C1-C8)-alkyl optionally substituted in the heteroaryl radical, or the radical R15;
R12b is amino, di-((C1-C18)-alkyl)-amino or R12axe2x80x94NH;
R13 is hydrogen or (C1-C6)-alkyl;
R15 is R16xe2x80x94(C1-C6)-alkyl or R16;
R16 is a 6-membered to 14-membered bicyclic or tricyclic radical which is saturated or partially unsaturated and which can also contain one, two, three or four identical or different heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur and which can also be substituted by one or more identical or different substituents selected from the group consisting of (C1-C4)-alkyl and oxo; Het is the radical of a 5-membered to 10-membered, saturated monocyclic or polycyclic heterocycle, bonded via a ring nitrogen atom, which can contain one, two, three or four identical or different additional ring heteroatoms selected from the group of oxygen, nitrogen and sulfur and which can optionally be substituted on carbon atoms and on additional ring nitrogen atoms, where substituents on additional ring nitrogen atoms can be identical or different radicals selected from the group of hydrogen, Rh, HCO, RhCO or RhOxe2x80x94CO and Rh is (C1-C8)-alkyl, (C3-C8)-cycloalkyl, (C3-C8)-cycloalkyl-(C1-C8)-alkyl, optionally substituted (C6-C14)-aryl or (C6-C14)-aryl-(C1-C8)-alkyl optionally substituted in the aryl radical;
e and h independently of one another are 0 or 1;
in all their stereoisomeric forms and mixtures thereof in all ratios, and their physiologically tolerable salts.
Very particularly preferred compounds of the formula I are those in which, simultaneously
W is R1xe2x80x94Axe2x80x94C(R13);
Z is oxygen;
A is a direct bond or methylene;
B is a divalent methylene radical or ethylene radical, both of which can be unsubstituted or can be substituted by a radical selected from the group consisting of (C1-C8)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl, (C3-C10)-cycloalkyl, (C3-C10)-cycloalkyl-(C1-C6)-alkyl, optionally substituted (C6-C14)-aryl, (C6C14)-aryl-(C1-C6)-alkyl, optionally substituted in the aryl radical, optionally substituted heteroaryl and heteroaryl-(C1-C6)-alkyl optionally substituted in the heteroaryl radical;
E is R10CO;
R is hydrogen or (C1-C4)-alkyl;
R0 is (C1-C8)-alkyl, (C3-C12)-cycloalkyl, (C3-C12)-cycloalkyl-(C1-C8)-alkyl, (C6-C12)-bicycloalkyl, (C6-C12)-bicycloalkyl-(C1-C8)-alkyl, (C6-C12)-tricycloalkyl, (C6-C12)-tricycloalkyl-(C1-C8)-alkyl, optionally substituted (C6-C14)-aryl, (C6-C14)-aryl-(C1-C8)-alkyl optionally substituted in the aryl radical, optionally substituted heteroaryl or heteroaryl-(C1-C8)-alkyl optionally substituted in the heteroaryl radical;
R1 is an optionally substituted radical selected from the group consisting of phenyl, furyl, thienyl, pyrrolyl, imidazolyl and pyridyl;
R2 is hydrogen or (C1-C4)-alkyl;
R3 is (C1-C8)-alkyl, optionally substituted (C6-C14)-aryl, (C6-C14)-aryl-(C1-C4)-alkyl optionally substituted in the aryl radical, optionally substituted heteroaryl, heteroaryl-(C1-C4)-alkyl optionally substituted in the heteroaryl radical, (C3-C8)-cycloalkyl, (C3-C8)-cycloalkyl-(C1-C4)-alkyl, (C6-C12)-bicycloalkyl, (C6-C12)-bicycloalkyl-(C1-C4)-alkyl, (C6-C12)-tricycloalkyl, (C6-C12)-tricycloalkyl-(C1-C4)-alkyl, R11NH, CON(CH3)R4, CONHR4, COOR15, CON(CH3)R15 or CONHR15;
R4 is (C1-C8)-alkyl which can optionally be monosubstituted or polysubstituted by identical or different radicals from the group consisting of hydroxyl, (C1-C8)-alkoxy, R5, optionally substituted (C3-C8)-cycloalkyl, hydroxycarbonyl, aminocarbonyl, mono- or di-((C1-C8)-alkyl)-aminocarbonyl, (C6-C14)-aryl-(C1-C8)-alkoxycarbonyl which can also be substituted in the aryl radical, (C1-C8)-alkoxycarbonyl, Het-CO, R6xe2x80x94CO, tetrazolyl and trifluoromethyl;
R5 is optionally substituted (C6-C14)-aryl, (C6-C14)-aryl-(C1-C8)-alkyl optionally substituted in the aryl radical or an optionally substituted monocyclic or bicyclic 5-membered to 12-membered heterocyclic ring, which can be aromatic, partially hydrogenated or completely hydrogenated and which can contain one, two or three identical or different heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur;
R6 is the radical of a natural or unnatural amino acid, imino acid or optionally Nxe2x80x94(C1-C8)-alkylated or Nxe2x80x94((C6-C14)-aryl-(C1-C8)-alkylated) azaamino acid which can also be substituted in the aryl radical, as well as their esters and amides, where free functional groups can be protected by protective groups customary in peptide chemistry;
R10 is hydroxyl, (C1-C8)-alkoxy, (C6-C14)-aryl-(C1-C8)-alkoxy which can also be substituted in the aryl radical, optionally substituted (C6-C14)-aryloxy, (C1-C8)-alkylcarbonyloxy-(C1-C6)-alkoxy, (C6-C14)-arylcarbonyloxy-(C1-C6)-alkoxy, amino or mono- or di-((C1-C8)-alkyl)-amino;
R11 is R12a, R12axe2x80x94CO, R12axe2x80x94Oxe2x80x94CO, R12bxe2x80x94CO or R12axe2x80x94S(O)2;
R12a is (C1-C10)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl, (C3-C12)-cycloalkyl, (C3-C12)-cycloalkyl-(C1-C8)-alkyl, optionally substituted (C6-C14)-aryl, (C6-C14)-aryl-(C1-C8)-alkyl optionally substituted in the aryl radical, optionally substituted heteroaryl, heteroaryl-(C1-C8)-alkyl optionally substituted in the heteroaryl radical, or the radical R15;
R12b is amino, di-((C1-C10)-alkyl)-amino or R12axe2x80x94NH;
R13 is hydrogen or (C1-C4)-alkyl;
R15 is R16xe2x80x94(C1-C3)-alkyl or R16;
R16 is a 7-membered to 12-membered bicyclic or tricyclic radical which is saturated or partially unsaturated and which can also contain one or two identical or different heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur and which can also be substituted by one or more identical or different substituents selected from the group consisting of (C1-C4)-alkyl and oxo;
Het is the radical of a 5-membered to 10-membered, saturated monocyclic or polycyclic heterocycle bonded via a ring nitrogen atom, which can contain one or two identical or different additional ring heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur and which can optionally be substituted on carbon atoms and additional ring nitrogen atoms, where substituents on additional ring nitrogen atoms can be identical or different radicals selected from the group consisting of hydrogen, Rh, HCO, RhCO or RhOxe2x80x94CO and Rh is (C1-C6)-alkyl, (C3-C8)-cycloalkyl, (C3-C8)-cycloalkyl-(C1-C4)-alkyl, optionally substituted (C6-C14)-aryl or (C6-C14)-aryl-(C1-C4)-alkyl optionally substituted in the aryl radical;
e and h independently of one another are 0 or 1;
in all their stereoisomeric forms and mixtures thereof in all ratios, and their physiologically tolerable salts.
Additionally preferred compounds of the formula I are those in which, simultaneously
W is R1xe2x80x94Axe2x80x94C(R13);
Z is oxygen;
A is a direct bond or methylene;
B is an unsubstituted methylene radical or a methylene radical which is substituted by a radical selected from the group consisting of (C1-C8)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl, (C3-C7)-cycloalkyl, (C3-C7)-cycloalkyl-(C1-C4)-alkyl, optionally substituted (C6-C10)-aryl, (C6-C10)-aryl-(C1-C4)-alkyl optionally substituted in the aryl radical, optionally substituted heteroaryl and heteroaryl-(C1-C4)-alkyl optionally substituted in the heteroaryl radical;
E is R10CO;
R is hydrogen or (C1-C4)-alkyl;
R0 is (C6-C14)-aryl-(C1-C4)-alkyl optionally substituted in the aryl radical or heteroaryl-(C1-C4)-alkyl optionally substituted in the heteroaryl radical;
R1 is an optionally substituted radical selected from the group consisting of phenyl, furyl, thienyl, pyrrolyl, imidazolyl and pyridyl;
R2 is hydrogen or (C1-C4)-alkyl;
R3 is an unsubstituted phenyl radical or naphthyl radical or a phenyl radical or naphthyl radical which is substituted by one, two or three identical or different radicals selected from the group consisting of (C1-C4)-alkyl, (C1-C4)-alkoxy, hydroxyl, halogen, trifluoromethyl, nitro, methylenedioxy, ethylenedioxy, hydroxycarbonyl, (C1-C4)-alkoxycarbonyl, aminocarbonyl, cyano, phenyl, phenoxy, benzyl and benzyloxy, or R3 is pyridyl, (C1-C4)-alkyl, (C2-C4)-alkenyl, (C2-C4)-alkynyl, (C5-C6)-cycloalkyl, R11NH, CON(CH3)R4, CONHR4, CON(CH3)R15 or CONHR15;
R4 is (C1-C8)-alkyl which is substituted by one or two identical or different radicals selected from the group consisting of hydroxyl, (C1-C8)-alkoxy, R5, optionally substituted (C3-C8)-cycloalkyl, hydroxycarbonyl, aminocarbonyl, (C6-C10)-aryl-(C1-C4)-alkoxycarbonyl which can also be substituted in the aryl radical, (C1-C6)-alkoxycarbonyl, Het-CO, R6xe2x80x94CO, tetrazolyl and trifluoromethyl;
R5 is optionally substituted (C6-C10)-aryl, (C6-C10)-aryl-(C1-C4)-alkyl optionally substituted in the aryl radical or an optionally substituted monocyclic or bicyclic 5-membered to 10-membered heterocyclic ring which can be aromatic, partially hydrogenated or completely hydrogenated and which can contain one, two or three identical or different heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur;
R10 is hydroxyl, (C1-C8)-alkoxy, (C6-C10)-aryl-(C1-C4)-alkoxy which can also be substituted in the aryl radical, optionally substituted (C6-C10)-aryloxy, (C1-C8)-alkylcarbonyloxy-(C1-C4)-alkoxy, (C6-C10)-arylcarbonyloxy-(C1-C4)-alkoxy, amino or mono- or di-((C1-C8)-alkyl)-amino;
R11 is R12a, R12axe2x80x94CO, R12axe2x80x94Oxe2x80x94CO, R12bxe2x80x94CO or R12axe2x80x94S(O)2;
R12a is (C1-C10)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl, (C3-C12)-cycloalkyl, (C3-C12)-cycloalkyl-(C1-C8)-alkyl, optionally substituted (C6-C14)-aryl, (C6-C14)-aryl-(C1-C8)-alkyl optionally substituted in the aryl radical, optionally substituted heteroaryl, heteroaryl-(C1-C8)-alkyl optionally substituted in the heteroaryl radical, or the radical R15;
R12b is amino, di-((C1-C10)-alkyl)-amino or R12axe2x80x94NH;
R13 is hydrogen or (C1-C4)-alkyl;
R15 is R16xe2x80x94(C1-C3)-alkyl or R16;
R16 is a 7-membered to 12-membered bicyclic or tricyclic radical which is saturated and which can also contain one or two identical or different heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur and which can also be substituted by one or more identical or different substituents from the group consisting of (C1-C4)-alkyl and oxo;
Het is the radical of a 5-membered to 7-membered, saturated monocyclic heterocycle bonded via a ring nitrogen atom, which can contain one or two identical or different additional ring heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur and which can be optionally substituted on carbon atoms and on additional ring nitrogen atoms, where substituents on additional ring nitrogen atoms can be identical or different radicals from the group consisting of hydrogen, Rh, HCO, RhCO or RhOxe2x80x94CO and Rh is (C1-C6)-alkyl, (C3-C8)-cycloalkyl, (C3-C8)-cycloalkyl-(C1-C4)-alkyl, optionally substituted (C6-C10)-aryl or (C6-C10)-aryl-(C1-C4)-alkyl optionally substituted in the aryl radical;
e and h independently of one another are 0 or 1;
in all their stereoisomeric forms and mixtures thereof in all ratios, and their physiologically tolerable salts.
Especially preferred compounds of the formula I are on the one hand those in which B is unsubstituted methylene or methylene which is substituted by a (C1-C8)-alkyl radical, in all their stereoisomeric forms and mixtures thereof in all ratios, and their physiologically tolerable salts. Particularly especially preferred compounds of the formula I are those in which B is methylene which is substituted by a (C1-C8)-alkyl radical, in all their stereoisomeric forms and mixtures thereof in all ratios, and their physiologically tolerable salts.
Especially preferred compounds of the formula I are on the other hand those in which R1 is a radical selected from the group of phenyl, furyl, thienyl, pyrrolyl, imidazolyl and pyridyl, which is unsubstituted or substituted by one, two or three identical or different substituents selected from the group consisting of (C1-C4)-alkyl, (C1-C4)-alkoxy, halogen, amino, trifluoromethyl, hydroxyl, hydroxy-(C1-C4)-alkyl, methylenedioxy, ethylenedioxy, phenyl, phenoxy, benzyl and benzyloxy, in all their stereoisomeric forms and mixtures thereof in all ratios, and their physiologically tolerable salts.
Particularly especially preferred compounds of the formula I are those in which R1 is a radical selected from the group of phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 3-pyrrolyl, 4-imidazolyl and 3-pyridyl and 4-pyridyl, where the phenyl radical is unsubstituted or substituted by one or two identical or different radicals selected from the group consisting of (C1-C4)-alkyl, (C1-C4)-alkoxy, halogen, trifluoromethyl, hydroxyl, hydroxy-(C1-C4)-alkyl, methylenedioxy, ethylenedioxy, phenyl, phenoxy, benzyl and benzyloxy and where the heteroaromatic radicals are unsubstituted or are substituted by one or two identical or different radicals selected from the group of (C1-C4)-alkyl, (C1-C4)-alkoxy, halogen, amino, trifluoromethyl, hydroxyl, hydroxy-(C1-C4)-alkyl, methylenedioxy, ethylenedioxy, phenyl, phenoxy, benzyl and benzyloxy, in all their stereoisomeric forms and mixtures thereof in all ratios, and their physiologically tolerable salts.
Very particularly especially preferred compounds of the formula I are those in which
R1 is an unsubstituted radical selected from the group of phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 3-pyrrolyl, 4-imidazolyl, 3-pyridyl and 4-pyridyl, in all their stereoisomeric forms and mixtures thereof in all ratios, and their physiologically tolerable salts.
Even more especially preferred compounds of the formula I are those in which R1 is an unsubstituted radical selected from the group of phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 4-imidazolyl and 4-pyridyl, in all their stereoisomeric forms and mixtures thereof in all ratios, and their physiologically tolerable salts.
Generally, compounds of the formula I are preferred which have a uniform configuration at chiral centers, for example on the chiral carbon atom carrying the radicals R2 and R3 when this atom is appropriately substituted, and/or on the center W in the imidazolidine ring in the formula I.
The compounds of the formula I can be prepared as desired, for example, by fragment condensation of a compound of the formula II 
with a compound of the formula III, 
where, in the formulae II and III, the groups W, Z, B, E, R, R0, R2 and R3 as well as e and h are defined as indicated above or alternatively in these groups functional groups can be present in protected form or in the form of precursors, and where G is hydroxycarbonyl, (C1-C6)-alkoxycarbonyl or activated carboxylic acid derivatives such as acid chlorides or active esters. If compounds of the formula I are to be prepared in which, for example, R3 in the formula I is a carboxylic acid derivative or contains such a derivative, it is also possible that in the compounds of the formula III the radical R3 initially is a hydroxycarbonyl group present in protected form or contains such a group in protected form, and that then the desired final group R3 is synthesized in one or more further steps only after the condensation of the compounds of the formulae II and III.
For the condensation of the compounds of the formula II with those of the formula III, the coupling methods of peptide chemistry well-known per se to the person skilled in the art are advantageously used (see, for example, Houben-Weyl, Methoden der Organischen Chemie [Methods of Organic Chemistry], Volume 15/1 and 15/2, Georg Thieme Verlag, Stuttgart, 1974), incorporated herein by reference. Possible condensing agents are, for example, carbonyldiimidazole, carbodiimides such as dicyclohexylcarbodiimide or diisopropylcarbodiimide, O-((cyano(ethoxycarbonyl)methylen)amino)-N,N,Nxe2x80x2,Nxe2x80x2-tetramethyluronium tetrafluoroborate (TOTU) or propylphosphonic anhydride (PPA). Generally, it is necessary in the condensation to protect nonreacting amino groups present by reversible protective groups. The same applies to carboxyl groups not involved in the reaction, which are preferably present during the condensation as (C1-C6)-alkyl esters, for example tert-butyl esters, or as benzyl esters. Amino group protection is unnecessary if the amino groups are still present in the form of precursors, for example as nitro groups, and are only formed after coupling, for example by hydrogenation. After coupling, the protective groups present are removed in a suitable manner. For example, NO2 groups (guanidino protection in amino acids), benzyloxycarbonyl groups and benzyl groups in benzyl esters can be removed by hydrogenation. The protective groups of the tert-butyl type are removed under acidic conditions, while the 9-fluorenylmethyloxycarbonyl radical is removed by secondary amines. The compounds of the formula I can also be prepared, for example, by synthesizing the compounds stepwise on a solid phase according to customary methods, where the individual structural elements of the molecule can be introduced in varying sequences.
Compounds of the formula II in which W is R1xe2x80x94Axe2x80x94C(R13) and Z is oxygen can be prepared, for example, by first reacting compounds of the formula IV 
in a Bucherer reaction to give compounds of the formula V 
in which, as well as in the formula IV, R1, R13 and A are defined as indicated above (H. T. Bucherer, V. A. Lieb, J. Prakt. Chem. 141(1934), 5).
Compounds of the formula VI 
in which R1, R13, A, B and G are defined as indicated above, can then be obtained by first reacting the compounds of the formula V, for example, with an alkylating reagent which introduces the radical xe2x80x94Bxe2x80x94G into the molecule. The reaction of compounds of the formula VI with a second reagent of the formula R0xe2x80x94LG, in which R0 has the meanings indicated above and LG is a nucleophilically substitutable leaving group, for example halogen, in particular chlorine or bromine, (C1-C4)-alkoxy, optionally substituted phenoxy or a heterocyclic leaving group such as, for example, imidazolyl, leads to the corresponding compounds of the formula II. These reactions can be carried out analogously to known methods familiar to the person skilled in the art. Depending on the individual case, it may be appropriate here, as in all steps in the synthesis of the compounds of the formula I, to temporarily block functional groups which could lead to secondary reactions or undesired reactions by means of a protective group strategy tailored to the synthesis problem, as is known to the person skilled in the art. With respect to the preparation of the compounds of the formulae V and VI in racemic form and in enantiomerically pure form, reference is in particular made here to the corresponding embodiments in WO-A-96/33976, which is hereby incorporated by reference in its entirety.
If W is R1xe2x80x94Axe2x80x94CHxe2x95x90C, this structural element can be introduced, for example, by condensing, analogously to known methods, an aldehyde with a dioxoimidazolidine or thioxo-oxoimidazolidine which contains an unsubstituted methylene group in the position corresponding to the group W.
The amino compounds of the formula III can be synthesized, according to or analogously to well-known standard procedures, from starting compounds which are commercially available or are obtainable according to or analogously to literature procedures.
Compounds of the formula I in which W is R1xe2x80x94Axe2x80x94C(R13) can also be obtained as follows:
By reaction of xcex1-amino acids or N-substituted xcex1-amino acids obtainable according to standard procedures or preferably their esters, for example the methyl ester, ethyl ester, tert-butyl ester or benzyl ester, for example of a compound of the formula VII 
in which R0, R1, R13 and A are defined as indicated above, with an isocyanate or isothiocyanate, for example of the formula VIII 
in which B, E, R, R2, R3, e and h are defined as indicated above and U is isocyanato or isothiocyanato, urea derivatives or thiourea derivatives of the formula IX 
are obtained for which the definitions indicated above apply, and which are cyclized by heating with acid with hydrolysis of the ester functions to give compounds of the formula Ia 
for which the meanings indicated above apply. The cyclization of the compounds of the formula IX to the compounds of the formula Ia can also be carried out by treatment with bases in inert solvents, for example by treatment with sodium hydride in an aprotic solvent such as dimethylformamide. During the cyclization, functional groups can in turn be present in protected form.
Compounds of the formula I in which W is R1xe2x80x94Axe2x80x94C(R13) can also be obtained by reacting a compound of the formula VII with an isocyanate or isothiocyanate of the formula X 
in which B and U are defined as indicated above for the formula VIII and Q is an alkoxy group, for example a (C1-C4)-alkoxy group such as methoxy, ethoxy or tert-butoxy, a (C6-C14)-aryloxy group, for example phenoxy, or a (C6-C14)-aryl-(C1-C4)-alkoxy group, for example benzyloxy. In this case a compound of the formula XI 
is obtained in which Z, A, B, Q, R0, R1 and R13 are defined as indicated above for the formulae IX and X, which is then cyclized under the influence of an acid or of a base, such as described above for the cyclization of the compounds of the formula IX, to give a compound of the formula XII 
in which W is R1xe2x80x94Axe2x80x94C(R13) and Z, B, Q and R0 are defined as indicated above for the formulae Ia and X. From the compound of the formula XII a compound of the formula Ia is then obtained by hydrolysis of the group COxe2x80x94Q to the carboxylic acid COOH and subsequent coupling with a compound of the formula III, as described above for the coupling of the compounds of the formulae II and III. Here too, during the cyclization functional groups can be present in protected form or in the form of precursors.
A further method for the preparation of compounds of the formula Ia is, for example, the reaction of compounds of the formula XIII 
in which W is R1xe2x80x94Axe2x80x94C(R13) and for which otherwise the definitions indicated above apply, with phosgene, thiophosgene or corresponding equivalents (analogously to S. Goldschmidt and M. Wick, Liebigs Ann. Chem. 575 (1952), 217-231 and C. Tropp, Chem. Ber. 61 (1928), 1431-1439).
With respect to the preparation of the compounds of the formula I, reference is furthermore fully made to WO-A-95/14008, EP-A-796 855 (European Patent Application 97103712.2) and the applications corresponding to it, as well as to WO-A-96/33976, all of which are incorpoorated by reference in their entireties.
The compounds of the formula I are valuable pharmaceutically active compounds which are suitable, for example, for the therapy and prophylaxis of inflammatory disorders, allergic disorders or asthma. The compounds of the formula I and their physiologically tolerable salts can be administered according to the invention to animals, preferably to mammals, and in particular to man, as pharmaceuticals for therapy or prophylaxis. They can be administered per se, in mixtures with one another or in the form of pharmaceutical preparations which permit enteral or parenteral administration and which as active constituent contain an efficacious dose of at least one compound of the formula I and/or its physiologically tolerable salts in addition to customary pharmaceutically innocuous excipients and/or additives.
The present invention therefore also relates to the compounds of the formula I and/or their physiologically tolerable salts for use as pharmaceuticals, the use of the compounds of the formula I and/or their physiologically tolerable salts for the production of pharmaceuticals for the therapy and prophylaxis of the diseases described above or in the following, for example for the therapy and prophylaxis of inflammatory disorders, and the use of the compounds of the formula I and/or their physiologically tolerable salts in the therapy and prophylaxis of these diseases. The present invention furthermore relates to pharmaceutical preparations which contain an efficacious dose of at least one compound of the formula I and/or its physiologically tolerable salts in addition to customary pharmaceutically innocuous excipients and/or additives.
The pharmaceuticals can be administered orally, for example in the form of pills, tablets, film-coated tablets, sugar-coated tablets, granules, hard and soft gelatin capsules, solutions, syrups, emulsions or suspensions. However, administration can also be carried out rectally, for example in the form of suppositories, or parenterally, for example in the form of injection or infusion solutions, microcapsules or rods, or percutaneously, for example in the form of ointments, solutions or tinctures, or in another way, for example in the form of nasal sprays or aerosol mixtures.
The pharmaceutical preparations according to the invention are prepared in a manner known per se, pharmaceutically inert inorganic or organic excipients being used in addition to the compound(s) of the formula I and/or its/their physiologically tolerable salts. For the preparation of pills, tablets, sugar-coated tablets and hard gelatin capsules, it is possible to use, for example, lactose, cornstarch or derivatives thereof, talc, stearic acid or its salts etc. Excipients for soft gelatin capsules and suppositories are, for example, fats, waxes, semisolid and liquid polyols, natural or hardened oils etc. Suitable excipients for the preparation of solutions, for example injection solutions, or of emulsions or syrups are, for example, water, alcohols, glycerol, polyols, sucrose, invert sugar, glucose, vegetable oils etc. Suitable excipients for microcapsules, implants or rods are, for example, copolymers of glycolic acid and lactic acid. The pharmaceutical preparations normally contain approximately 0.5 to 90% by weight of the compounds of the formula I and/or their physiologically tolerable salts.
In addition to the active compounds and excipients, the pharmaceutical preparations can additionally contain additives, such as, for example, fillers, disintegrants, binders, lubricants, wetting agents, stabilizers, emulsifiers, preservatives, sweeteners, colorants, flavorings or aromatizers, thickeners, diluents, buffer substances, and also solvents or solubilizers or means for achieving a depot effect, as well as salts for altering the osmotic pressure, coating agents or antioxidants. They can also contain two or more compounds of the formula I and/or their physiologically tolerable salts. Furthermore, they can also contain one or more other therapeutically or prophylactically active substances in addition to at least one compound of the formula I and/or its physiologically tolerable salts, for example substances having antiinflammatory action. The pharmaceutical preparations normally contain 0.2 to 500 mg, preferably 1 to 100 mg, of active compound of the formula I and/or its physiologically tolerable salts.
The compounds of the formula I have the ability to inhibit cell-cell and cell-matrix interaction processes in which interactions between VLA-4 with its ligands play a part. The efficacy of the compounds of the formula I can be demonstrated, for example, in an assay in which the binding of cells which contain the VLA-4 receptor, for example of leucocytes, to ligands of this receptor is measured, for example to VCAM-1, which for this purpose can advantageously also be prepared by genetic engineering. Details of such an assay are described below. In particular, the compounds of the formula I are able to inhibit the adhesion and the migration of leucocytes, for example the adhesion of leucocytes to endothelial cells whichxe2x80x94as explained abovexe2x80x94is controlled via the VCAM-1/VLA-4 adhesion mechanism. Besides as antiinflammatory agents, the compounds of the formula I and their physiologically tolerable salts are therefore generally suitable for the therapy and prophylaxis of diseases which are based on the interaction between the VLA-4 receptor and its ligands or can be affected by an inhibition of this interaction, and in particular they are suitable for the therapy and prophylaxis of diseases which are caused at least partially by an undesired extent of leucocyte adhesion and/or leucocyte migration or are associated therewith, or for whose prevention, alleviation or cure the adhesion and/or migration of leucocytes should be decreased.
The compounds of the formula I can be employed as antiinflammatories in the case of a variety of inflammatory symptoms. They are used, for example, for the therapy or prophylaxis of rheumatoid arthritis, of inflammatory bowel disease (ulcerative colitis), of systemic lupus erythematosus or for the therapy or prophylaxis of inflammatory disorders of the central nervous system such as, for example, multiple sclerosis, for the therapy or prophylaxis of asthma or of allergies, for example allergies of the delayed type (type IV allergy). They are furthermore suitable for the therapy or prophylaxis of cardiovascular disorders, arteriosclerosis, of restenoses, for the therapy or prophylaxis of diabetes, for the prevention of damage to organ transplants, for the inhibition of tumor growth or formation of tumor metastases in various malignancies, for the therapy of malaria as well as of other diseases in which blocking of the integrin VLA-4 and/or influencing of the leucocyte activity appears appropriate for prevention, alleviation or cure.
The dose when using the compounds of the formula I can vary within wide limits and is to be tailored to the individual conditions in each individual case as is customary. The dose depends, for example, on the compound employed or on the nature and severity of the disease to be treated or on whether an acute or chronic disease state is treated or whether prophylaxis is conducted. In general, in the case of oral administration a daily dose of approximately 0.01 to 100 mg/kg, preferably 0.1 to 10 mg/kg, in particular 0.3 to 2 mg/kg (in each case per kg of body weight) is appropriate in an adult weighing about 75 kg to achieve effective results. In the case of intravenous administration, the daily dose is in general approximately 0.01 to 50 mg/kg, preferably 0.01 to 10 mg/kg of body weight. In particular when relatively large amounts are administered, the daily dose can be divided into a number of, for example 2, 3 or 4, part administrations. If appropriate, depending on individual behavior, it may be necessary to deviate upward or downward from the indicated daily dose.
The present invention therefore also relates to the compounds of the formula I for the inhibition of the adhesion and/or migration of leucocytes or for the inhibition of the VLA-4 receptor and the use of the compounds of the formula I for the production of pharmaceuticals therefor, i.e., of pharmaceuticals for the therapy or prophylaxis of diseases in which leucocyte adhesion and/or leucocyte migration exhibits an undesired extent, or of diseases in which VLA-4-dependent adhesion processes play a part, as well as the use of the compounds of the formula I and/or their physiologically tolerable salts in the therapy and prophylaxis of diseases of this type.
The compounds of the formula I and their salts can furthermore be employed for diagnostic purposes, for example in in-vitro diagnoses, and as auxiliaries in biochemical investigations in which VLA-4 blocking or influencing of cell-cell or cell-matrix interactions is intended. They can furthermore be used as intermediates for the preparation of other compounds, in particular of other pharmaceutically active compounds which are obtainable from the compounds of the formula I, for example, by modification or introduction of radicals or functional groups.